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&#40;a&#41; adherence to plastic under standard culture conditions&#44; &#40;b&#41; expression of CD105&#44; CD73&#44; and CD90&#44; and lack of expression of CD45&#44; CD34&#44; CD14 or CD11b&#44; CD79a or CD19&#44; and HLA-DR surface molecules&#44; and &#40;c&#41; the ability to differentiate into osteoblasts&#44; adipocytes&#44; and chondroblasts in vitro&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Additionally&#44; MSCs are considered immunoprivileged cells&#44; as they do not express major histocompatibility complex &#40;MHC&#41; II or co-stimulatory molecules such as CD86&#44; CD40&#44; or CD80&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">Although present in minute quantities in the body&#44; MSCs play a key role in tissue homeostasis through their regenerative&#44; anti-inflammatory&#44; anti-oxidative stress&#44; antimicrobial&#44; antifibrotic&#44; antiapoptotic&#44; or antitumor effects&#46; These positive effects are achieved through the secretion of cytokines&#44; growth factors&#44; and even extracellular vesicles &#40;EVs&#41;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#8211;12</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The functional capacity of MSCs may be attributed to their derivation from the mesoderm&#44; a highly functional embryological layer&#44; similar to the immune and circulatory systems&#46; Evidence suggests that the mesoderm evolves to form a stroma intimately interconnected with tissues derived from the ectoderm or endoderm&#46; Although MSCs exhibit perivascular localization in different anatomical locations&#44; their functional capacity to generate paracrine signals varies&#46;<a class="elsevierStyleCrossRef" href="#bib0065"><span class="elsevierStyleSup">13</span></a> Therefore&#44; the functional heterogeneity of MSCs appears to reflect their adaptation to interact functionally with the microenvironment of different tissues and organs&#46;<a class="elsevierStyleCrossRefs" href="#bib0055"><span class="elsevierStyleSup">11&#44;12&#44;14</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">The concept of MSC dysfunction in systemic diseases arose from the observation that patients with autoimmune diseases such as systemic lupus erythematosus &#40;SLE&#41;&#44; diabetes mellitus &#40;DM&#41;&#44; rheumatoid arthritis &#40;RA&#41;&#44; multiple sclerosis&#44; or psoriasis entered remission when treated with allogeneic transplantation of MSCs or hematopoietic stem cells&#44; but not after autologous transplants&#46; Based on these findings&#44; which occurred in the context of leukemia or lymphoma treatment&#44;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> it has been hypothesized that in these cases&#44; the remission of systemic disease occurred due to the &#8220;resetting&#8221; of immune memory&#46; However&#44; it could also be due to the restoration of internal homeostasis by administering normally functional MSCs from healthy donors&#46; In this sense&#44; it is now becoming evident that depletion or dysfunction of such cells may underlie the pathophysiology of diseases such as SLE&#44; DM&#44; RA&#44; multiple sclerosis&#44; idiopathic pulmonary fibrosis&#44; Parkinson&#39;s disease&#44; amyotrophic lateral sclerosis&#44; psoriasis&#44; myelodysplastic syndromes&#44; or premature aging syndromes&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a> Moreover&#44; these systemic diseases associated with MSC dysfunction are characterized by the perpetuation of inflammatory states&#44; constant emission of &#8220;alarm signals&#44;&#8221; proliferation&#44; mobilization&#44; and&#44; ultimately&#44; an endless sequestration of MSCs in damaged tissues&#44; likely leading to depletion of this important type of specialized homeostatic and reparative cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0080"><span class="elsevierStyleSup">16&#44;17</span></a></p><p id="par0035" class="elsevierStylePara elsevierViewall">Based on these findings&#44; we can propose the hypothesis that an inadequate response by MSCs to alarm signals from damaged somatic cells could contribute to a loss of control of tissue homeostasis &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>A&#41;&#46; This situation could be due to the exhaustion or depletion of exhausted MSCs &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>B&#41;&#44; or their primary or secondary cellular dysfunction induced by alterations in the tissue microenvironment &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>C&#41;&#46; Thus&#44; considering this new pathophysiological paradigm may serve as the basis for developing new therapeutic alternatives using MSCs or biological products derived from their secretome&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><elsevierMultimedia ident="fig0010"></elsevierMultimedia></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Era of mesenchymal stem cell-based cell therapy&#58; expectations&#44; results&#44; and limitations</span><p id="par0040" class="elsevierStylePara elsevierViewall">Bone marrow&#44; subcutaneous fat&#44; Wharton&#39;s jelly&#44; and umbilical cords are the most commonly used sources of MSCs&#46; However&#44; other origins such as fetal&#47;neonatal tissues&#44; dental pulp&#44; or those of uterine and reproductive origin<a class="elsevierStyleCrossRefs" href="#bib0075"><span class="elsevierStyleSup">15&#44;18</span></a> are gaining increasing interest&#46;<a class="elsevierStyleCrossRef" href="#bib0095"><span class="elsevierStyleSup">19</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In addition to the classic research and clinical applications of MSCs&#44; such as in osteogenesis imperfecta&#44;<a class="elsevierStyleCrossRef" href="#bib0100"><span class="elsevierStyleSup">20</span></a> graft-versus-host disease &#40;GVHD&#41;&#44;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> multiple sclerosis&#44;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a> strokes&#44;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> osteoarthritis&#44;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> liver cirrhosis&#44;<a class="elsevierStyleCrossRef" href="#bib0125"><span class="elsevierStyleSup">25</span></a> cardiovascular disease&#44;<a class="elsevierStyleCrossRef" href="#bib0130"><span class="elsevierStyleSup">26</span></a> or Crohn&#39;s disease&#44;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a> the wide range of possible applications of MSCs and&#47;or their secretome is constantly expanding&#46; As of July 21&#44; 2023&#44; 1315 interventional clinical trials &#40;see ClinicalTrials&#46;gov&#41; have been registered in various indications&#46; However&#44; despite all these positive findings&#44; there are significant limitations&#44; including the use of an invasive isolation method&#44; difficulty in cultivating cells in sufficient quantities&#44; immunological incompatibility&#44; tumor or embolus formation&#44; potential transmission of infections&#44; entry into senescence&#44; difficult evaluation of safety&#44; dosage&#44; and potency&#44; complex storage conditions&#44; high economic costs&#44; impractical clinical use&#44; difficult availability of large quantities for immediate use&#44; and biological heterogeneity of cells in relation to the donor and tissue origin&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;29&#8211;31</span></a> All these factors make it challenging for this new type of medicine to be generalized&#46; Therefore&#44; it is necessary to find new strategic alternatives in the context of MSC-based medicine&#46;</p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Possibility of cell-free therapy based on the secretome of mesenchymal stem cells</span><p id="par0050" class="elsevierStylePara elsevierViewall">Initially&#44; the therapeutic effects of MSCs were attributed to their grafting and differentiation capacity&#46; However&#44; it has been subsequently demonstrated that the implantation period of MSCs is usually too short to have an effective impact&#46;<a class="elsevierStyleCrossRefs" href="#bib0160"><span class="elsevierStyleSup">32&#44;33</span></a> In fact&#44; less than 1&#37; of MSCs are reported to survive more than a week after systemic administration&#44;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> suggesting that the main effects of MSCs are mediated by paracrine mechanisms through components present in their secretome&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> The secretome of MSCs can be obtained in vitro under cell culture conditions &#40;referred to as conditioned medium&#41;&#44; containing a wide range of soluble bioactive factors &#40;growth factors&#44; cytokines&#44; or chemokines&#41; and extracellular vesicles &#40;EVs&#41;&#46; In addition to avoiding the drawbacks of cell therapy&#44; this offers new significant advantages&#44; such as a better evaluation of the product regarding safety&#44; dosage&#44; and potency&#44; similar to conventional therapeutic agents&#59; simpler storage without the need for cryoprotective agents&#59; and a more economical and practical approach for clinical use&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a> Furthermore&#44; the importance of a particularly relevant component of the MSC secretome&#44; namely EVs&#44;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> should be emphasized&#46; These microvesicles are surrounded by a membrane and contain a diverse range of components&#44; such as RNA&#44; lipids&#44; and proteins&#44; including cytokines&#44; chemokines&#44; interleukins&#44; integrins&#44; tetraspanins &#40;CD81&#44; CD63&#44; and CD9&#41;&#44; transport proteins&#44; signal transduction factors &#40;kinases&#41;&#44; cytoskeleton proteins&#44; and metabolic enzymes&#46; EVs are classified based on their origin into exosomes &#40;70&#8211;150<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; derived from the endosomal compartment corresponding to the intraluminal vesicles of multivesicular endosomes&#59; microvesicles &#40;100&#8211;1000<span class="elsevierStyleHsp" style=""></span>nm&#41;&#44; which are budding from the plasma membrane&#59; and apoptotic bodies&#44; larger fragments of apoptotic cells &#40;500&#8211;2000<span class="elsevierStyleHsp" style=""></span>nm&#41;&#46; Exosomes are less complex and immunogenic than their parent cells&#44; as they have a lower content of membrane-bound proteins&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Moreover&#44; the production and storage of exosomes are easier than for MSCs&#46;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> Other advantages of exosomes include a longer half-life in the bloodstream&#44; the ability to cross the blood-brain barrier&#44; and tropism towards inflamed tissues and tumors&#46;<a class="elsevierStyleCrossRefs" href="#bib0200"><span class="elsevierStyleSup">40&#44;41</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">In vitro and in vivo studies on the secretomes of MSCs have been rapidly increasing in recent years&#44; demonstrating that these biological products reproduce the effects of their parent cells&#44; suggesting a new therapeutic strategy<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;29</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0015">Fig&#46; 3</a>&#41;&#46;</p><elsevierMultimedia ident="fig0015"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">New concepts and challenges of a mesenchymal stem cell therapeutic strategy 2&#46;0 based on the products of its secretome</span><p id="par0060" class="elsevierStylePara elsevierViewall">From the review of specialized literature&#44; a prospective vision of the evolution of research and potential applications of MSCs in the last two decades can be observed&#58; from purely regenerative interest to their potential anti-inflammatory and other actions such as pro-angiogenic&#44; anti-oxidative stress&#44; anti-microbial&#44; or anti-tumoral&#59; from initially autologous transplantation to allogeneic&#59; and from cell therapy to the possibility of a cell-free therapy based on products derived from its secretome&#46; Likewise&#44; we can anticipate a series of challenges that will need to be addressed to bring this latter proposal to the forefront of patient care&#58; considering the importance of the functional heterogeneity of MSCs&#44; industrial production and standardization of their secretome&#44; and the possibility of inducing modifications in its composition for more specific therapeutic applications in a new MSC-based medicine that we can consider as 2&#46;0&#46;</p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Heterogeneity of mesenchymal stem cells</span><p id="par0065" class="elsevierStylePara elsevierViewall">The non-consideration of the functional heterogeneity of MSCs has been one of the reasons for the disparity of results in translating the therapeutic interest of MSCs into the clinic&#46; However&#44; this biological reality should rather represent a key strategic opportunity to choose the most appropriate MSC for each therapeutic indication&#46; The functional capacity of MSCs varies depending on their tissue or organ origin&#44; donor characteristics&#44; and the conditions of the artificial niche in culture and expansion&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Origin-dependent heterogeneity</span><p id="par0070" class="elsevierStylePara elsevierViewall">The functional heterogeneity of MSCs reflects the diversity of environments present in their natural niches&#44; which differ widely in the dynamics of communication between various cell communities&#44; chemical conditions&#44; and mechanical conditions of their tissue microenvironment&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> Consequently&#44; differences have been reported between MSCs from different origins regarding their proliferation capacity&#44; transdifferentiation&#44; or immunophenotype&#46; This functional heterogeneity of MSCs is also reflected in variations in the production of their secretome&#44; including microvesicles&#44; and therefore&#44; it is something to consider for the various potential therapeutic applications of these biological products&#46; All of this leads us to conceive the importance of new sources of MSCs that&#44; in addition to those traditionally considered&#44; can open up a range of more specific therapeutic possibilities&#46;<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a> An example of this is the identification by our Group of a new source of MSCs in the human uterine cervix &#40;hUCESC - &#8220;human Uterine Cervical Stem Cell&#8221;&#41;&#46; These cells can be easily obtained by cytology or from hysterectomy specimens&#46; Once extracted&#44; they show a high proliferative rate in culture&#44; allowing them to be obtained in large quantities compared to other types of MSCs&#46; In addition&#44; their secretome&#44; or conditioned medium&#44; obtained under culture conditions&#44; contains substances with regenerative&#44; anti-inflammatory&#44; immunoregulatory&#44; antimicrobial&#44; oxidative stress-reducing&#44; and anticancer properties&#44; more potent than those obtained from MSCs of other origins&#44; such as widely used adipose tissue-derived MSCs&#46;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#8211;47</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The potential presented by hUCESC and its secretome could be related to its origin in the human body&#46; hUCESC is obtained from the uterine cervix&#44; an area that is a gateway to the uterine cavity &#40;&#8220;the chest of life&#8221;&#41;&#44; and is constantly exposed to harmful elements present in the vagina&#44; such as a proinflammatory acidic environment&#44; bacteria and fungi that colonize it&#44; or viruses like human papillomavirus&#44; which plays a prominent role in cancer development&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Thus&#44; the existence in this area of cells that possess the ability to produce a cocktail of substances that protect it seems reasonable&#46;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Donor-dependent heterogeneity</span><p id="par0085" class="elsevierStylePara elsevierViewall">In addition to MSC dysfunction in relation to the existence of systemic diseases&#44; there are other causes of donor-dependent heterogeneity&#46; It is known that when theoretically identical populations of MSCs from different healthy individuals are compared&#44; they can show different properties of the secretome&#46;<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> The age and obesity of the donor are determining factors in this regard&#44; especially for MSCs from adipose tissue&#46; Although adipose tissue is considered an important reservoir of stem cells&#44; there is evidence indicating that MSCs from this origin in obese patients show less differentiation potential and fewer proangiogenic capabilities than those from non-obese individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0205"><span class="elsevierStyleSup">41&#44;50</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">MSCs collected from older donors are characterized by a higher percentage of apoptotic cells and a slower proliferation rate&#46; In addition&#44; MSCs derived from bone marrow or adipose tissue obtained from older individuals have reduced immunomodulatory properties and an also reduced capacity to respond to oxidative stress<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;52</span></a> compared to MSCs from younger individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0265"><span class="elsevierStyleSup">53</span></a> However&#44; even MSCs isolated from young and healthy donors show marked differences in their proliferation rate&#44; differentiation capacity&#44; and clinical utility&#46; For example&#44; significant differences in proliferative and transdifferentiation capacities have been described between MSCs from healthy donors and between samples obtained from the same donor but from different source locations&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Production&#44; standardization&#44; and modification of the secretome of mesenchymal stem cells</span><p id="par0095" class="elsevierStylePara elsevierViewall">Given the undeniable scientific and technological value of the secretome derived from MSCs and its likely high future demand&#44; the need to establish its in vitro production on an industrial scale becomes imperative&#46; Fortunately&#44; we now have the necessary technology&#44; such as bioreactors&#44; which allows for more precise and optimized control of the physicochemical conditions of cell cultures and large-scale production of products derived from their secretome&#46; These bioengineering systems combine materials that enable high cell culture density&#44; control of hydrodynamic parameters and agitation of the culture medium&#44; as well as precise control of chemical parameters or nutrient gradients<a class="elsevierStyleCrossRefs" href="#bib0145"><span class="elsevierStyleSup">29&#44;55&#44;56</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0020">Fig&#46; 4</a>&#41;&#46; Additionally&#44; there is the possibility of establishing ex vivo conditions that can cause modifications of the MSC secretome oriented towards more specific therapeutic applications&#44; such as O2 concentration&#44; 3D culture systems&#44; pre-conditioning methods&#44; or genetic manipulation&#46;</p><elsevierMultimedia ident="fig0020"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall">Cells are generally cultured in vitro under an O2 tension like that present in our atmosphere &#40;21&#37;&#41;&#46; However&#44; several studies have shown that MSCs cultured at low O2 concentrations&#44; which are more representative of tissues&#44; better retain their proliferative capacity&#44; surface antigen expression&#44; and differentiation potential&#44; compared to those cultured at atmospheric O2 tension&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;19&#44;57&#8211;60</span></a> Conventional cell culture is generally carried out in a two-dimensional &#40;2D&#41; system where cells grow as monolayers&#46; However&#44; it has been reported that MSCs cultured as 3D spheroids have significantly superior properties in their secretome compared to those obtained in 2D MSC cultures&#44; such as increased production of angiogenic factors or anti-cancer proteins&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;61&#8211;63</span></a> Moreover&#44; MSCs transfected with anti-inflammatory genes such as IL-10&#44; HGF&#44; IDO&#44; or Foxp3 enhance the anti-inflammatory potency of their secretome&#46;<a class="elsevierStyleCrossRefs" href="#bib0320"><span class="elsevierStyleSup">64&#8211;66</span></a> Overexpression of BDNF or interferon-beta induces a significantly greater neuroprotective effect than native MSCs and enhances the antitumor effect on glioma cells&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;67</span></a> Despite positive data on the genetic manipulation of MSCs&#44; there are aspects that limit their clinical application due to safety issues&#44; including potential tumorigenicity&#44; toxicity&#44; and immunogenicity derived from the use of viral agents&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a> Therefore&#44; the Clustered Regularly Interspaced Short Palindromic Repeats &#40;CRISPR&#41;-Cas9 genome editing technology can improve the therapeutic potential of the secretome with greater safety for the patient&#46;<a class="elsevierStyleCrossRef" href="#bib0345"><span class="elsevierStyleSup">69</span></a> Specific functional tests&#44; in vitro and&#47;or in vivo&#44; may be of interest to ensure the homogeneity of the action of these products derived from the MSC secretome before clinical applications&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">New challenges of therapeutic applications of mesenchymal stem cell technology 2&#46;0</span><p id="par0105" class="elsevierStylePara elsevierViewall">The availability of such a versatile biological product opens the possibility of a wide range of therapeutic potentialities&#46; There is the possibility of developing formulations adapted for the topical treatment of multifactorial diseases with complex physiopathology&#44; such as dry eye<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> syndrome or inflammatory bowel disease&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> In relation to the former&#44; our preclinical results showed that the topical installation of an eye drop based on the conditioned medium of hUCESC &#40;MC-hUCESC&#41; induced potent regenerative and anti-inflammatory effects in the damaged cornea of animals&#44;<a class="elsevierStyleCrossRefs" href="#bib0215"><span class="elsevierStyleSup">43&#44;45&#44;72</span></a> as well as in an experimental model of uveitis&#46; Inflammatory bowel diseases&#44; such as ulcerative colitis and Crohn&#39;s disease&#44; which are chronic and of unknown etiology&#44; have increased their incidence in the population up to 30 times in recent decades&#46; MSCs are a therapeutic alternative for these processes&#46;<a class="elsevierStyleCrossRef" href="#bib0365"><span class="elsevierStyleSup">73</span></a> As demonstrated by our in vivo data in a murine experimental model of colitis&#44; topical application using enemas of a combination of MC-hUCESC with a mucoadhesive hydrogel demonstrated potent anti-inflammatory and regenerative effects&#46; In mice treated with this innovative product&#44; our results not only showed a radical improvement in all histological parameters of colitis &#40;inflammation&#44; ulceration&#44; atrophy&#44; and dysplasia&#41; but also a decrease in the gene expression of inflammatory cytokines&#44; such as TNF-alpha&#44; IL-6&#44; or interferon-gamma&#44; which have been shown to play a very special role in the complex physiopathology of inflammatory bowel disease&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">Cancer continues to experience an unstoppable increase in its incidence&#44; estimated to go from 14 million new cases in 2012 to 19 million in 2025&#44; generating a 50&#37; mortality rate overall&#46; MSCs derived from reproductive tissues&#44; such as the uterus&#44; placenta&#44; or umbilical cord or amniotic fluid&#44; have shown anti-tumor activity against a wide variety of malignant tumors&#46; These effects may be due to highly present soluble elements in their secretomes that induce inhibition of tumor growth&#44;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> but also&#44; in part&#44; to exosomes with a recognized anti-tumor effect&#46; This is especially relevant when considering three fundamental aspects&#58; i&#41; cancer cells internalize a large percentage of exosomes compared to normal cells<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;63</span></a>&#59; ii&#41; there is a demonstrated tropism of these microvesicles toward tumors&#59; and iii&#41; the possibility of loading these particles with anti-tumor agents&#44; such as anti-cancer cytokines&#44; oncolytic viruses&#44; or chemotherapeutics&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a> In this nanotechnological context&#44; exosomes can represent innovative &#8220;Trojan horses&#8221; in the conception of a new&#44; sophisticated&#44; and selective anti-tumor strategy&#46;</p><p id="par0115" class="elsevierStylePara elsevierViewall">The fight against infections is becoming a real challenge for medicine&#46; According to epidemiologists&#39; estimates&#44; by the year 2030&#44; 13 million deaths worldwide will occur due to antibiotic resistance&#46; Preliminary results demonstrate the bactericidal<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a> or antifungal activity<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> of the MSC secretome&#46; This may be because the MSC secretome contains high concentrations of cytokines with recognized antibacterial<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> and antifungal effects&#46;<a class="elsevierStyleCrossRef" href="#bib0370"><span class="elsevierStyleSup">74</span></a> Additionally&#44; the MSC secretome may be very useful in trying to counteract the effects of the inflammatory storm caused by viral infection&#46;<a class="elsevierStyleCrossRef" href="#bib0375"><span class="elsevierStyleSup">75</span></a> Currently&#44; long-term results are being collected on the positive therapeutic effect of MSC transplantation or products derived from their secretome in critically ill patients with this disease&#44; which at least for now show positive safety data&#46;<a class="elsevierStyleCrossRef" href="#bib0380"><span class="elsevierStyleSup">76</span></a> This justifies the extraordinary interest in the development of this new biotechnology for future viral pandemics&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The initiative of a cell-free regenerative medicine can also allow us to address the challenge of healthier aging by alleviating diseases associated with this biological process&#44; such as cardiovascular&#44; neurodegenerative&#44; or osteoarticular diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">77</span></a> In this context&#44; we believe that a strategy of restoring the disrupted homeostatic balance through the administration of products secreted by MSCs has a place&#46;<a class="elsevierStyleCrossRef" href="#bib0390"><span class="elsevierStyleSup">78</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Conclusions</span><p id="par0125" class="elsevierStylePara elsevierViewall">The possibility of using products derived from the secretome of MSCs is placed in the context of the current needs of medicine&#44; where the complex pathophysiological reality of diseases renders the classic therapeutic concept of the pharmaceutical industry&#44; &#8220;one disease&#44; one therapeutic target&#44;&#8221; insufficient&#46; The real answer to this challenge is believed to lie in nature&#59; as Albert Einstein stated&#44; &#8220;Look deep into nature&#44; and then you will understand everything better&#46;&#8221;</p><p id="par0130" class="elsevierStylePara elsevierViewall">MSCs are increasingly recognized as key elements in internal homeostasis through their paracrine effect by producing a cocktail of factors with regenerative&#44; anti-inflammatory&#44; anti-oxidative stress&#44; antimicrobial&#44; or antitumor effects&#46; However&#44; cell therapy based on the transplantation of these cells faces the general disadvantages of cell therapy&#44; which include all the inconveniences of transplanting proliferating live cells&#46; Nevertheless&#44; a 2&#46;0 MSC technology is emerging&#44; representing a disruptive innovation that allows the implementation of a cell-free regenerative medicine&#46; This is based on the availability of a biological derivative like the MSC secretome&#46; This product can be produced in large quantities&#44; formulated specifically for many types of possible therapeutic applications&#44; and serve as the basis for future research and technological developments that represent a source of innovation in medicine&#46; The demanding requirements of regulatory agencies are well known&#44; but there are protocols and procedures that represent reasonable &#8220;roadmaps&#8221; to progressively bring this technology closer to the interest of therapeutic medicine&#46; The only failure is not to try&#33;</p></span></span>"
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          "titulo" => "Definition and concept of mesenchymal stem cells&#58; from their role in cellular homeostasis to the importance of their dysfunction in systemic diseases"
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          "titulo" => "Era of mesenchymal stem cell-based cell therapy&#58; expectations&#44; results&#44; and limitations"
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          "titulo" => "Possibility of cell-free therapy based on the secretome of mesenchymal stem cells"
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          "titulo" => "New concepts and challenges of a mesenchymal stem cell therapeutic strategy 2&#46;0 based on the products of its secretome"
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        9 => array:2 [
          "identificador" => "sec0030"
          "titulo" => "Heterogeneity of mesenchymal stem cells"
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          "titulo" => "Origin-dependent heterogeneity"
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          "identificador" => "sec0040"
          "titulo" => "Donor-dependent heterogeneity"
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        12 => array:2 [
          "identificador" => "sec0045"
          "titulo" => "Production&#44; standardization&#44; and modification of the secretome of mesenchymal stem cells"
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          "identificador" => "sec0050"
          "titulo" => "New challenges of therapeutic applications of mesenchymal stem cell technology 2&#46;0"
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          "identificador" => "sec0055"
          "titulo" => "Conclusions"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Stem cells of mesenchymal origin &#40;MSC&#41; arouse special interest due to their regenerative&#44; anti-inflammatory&#44; anti-apoptotic&#44; anti-oxidative stress&#44; antitumor or antimicrobial properties&#46; However&#44; its implementation in the clinic runs into drawbacks of cell therapy &#40;immunological incompatibility&#44; tumor formation&#44; possible transmission of infections&#44; entry into cellular senescence&#44; difficult evaluation of safety&#44; dose and potency&#59; complex storage conditions&#44; high economic cost or impractical clinical use&#41;&#46; Considering that the positive effects of MSC are due&#44; to a large extent&#44; to the paracrine effects mediated by the set of substances they secrete &#40;growth factors&#44; cytokines&#44; chemokines or microvesicles&#41;&#44; the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy&#46; However&#44; this new therapeutic innovation implies challenges&#44; such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome&#46;</p></span>"
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            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:1 [
                  "referenciaCompleta" => "Vol&#46; no&#46; 430&#46; &#40;UN&#44; New York&#44; 2019&#41;&#46;"
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Age associated oxidative damage in lymphocytes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "N&#46; Gautam"
                            1 => "S&#46; Das"
                            2 => "S&#46;K&#46; Mahapatra"
                            3 => "S&#46;P&#46; Chakraborty"
                            4 => "P&#46;K&#46; Kundu"
                            5 => "S&#46; Roy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.4161/oxim.3.4.12860"
                      "Revista" => array:5 [
                        "tituloSerie" => "Oxid Med Cell Longev&#46;"
                        "fecha" => "2010"
                        "volumen" => "3"
                        "paginaInicial" => "275"
                        "paginaFinal" => "282"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Health in an ageing world&#8211;what do we know&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46; Suzman"
                            1 => "J&#46;R&#46; Beard"
                            2 => "T&#46; Boerma"
                            3 => "S&#46; Chatterji"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0140-6736(14)61597-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet&#46;"
                        "fecha" => "2015"
                        "volumen" => "385"
                        "paginaInicial" => "484"
                        "paginaFinal" => "486"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/25468156"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical outcomes associated with medication regimen complexity in older people&#58; a systematic review"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "B&#46;C&#46; Wimmer"
                            1 => "A&#46;J&#46; Cross"
                            2 => "N&#46; Jokanovic"
                            3 => "M&#46;D&#46; Wiese"
                            4 => "J&#46; George"
                            5 => "K&#46; Johnell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1111/jgs.14682"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Am Geriatr Soc&#46;"
                        "fecha" => "2017"
                        "volumen" => "65"
                        "paginaInicial" => "747"
                        "paginaFinal" => "753"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/27991653"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Osteogenesis in transplants of bone marrow cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46;J&#46; Friedenstein"
                            1 => "I&#46;I&#46; Piatetzky-Shapiro"
                            2 => "K&#46;V&#46; Petrakova"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Embryol Exp Morphol&#46;"
                        "fecha" => "1966"
                        "volumen" => "16"
                        "paginaInicial" => "381"
                        "paginaFinal" => "390"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5336210"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Minimal criteria for defining multipotent mesenchymal stromal cells&#46; The International Society for Cellular Therapy position statement"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46; Dominici"
                            1 => "K&#46; Le Blanc"
                            2 => "I&#46; Mueller"
                            3 => "I&#46; Slaper-Cortenbach"
                            4 => "F&#46; Marini"
                            5 => "D&#46; Krause"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/14653240600855905"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cytotherapy&#46;"
                        "fecha" => "2006"
                        "volumen" => "8"
                        "paginaInicial" => "315"
                        "paginaFinal" => "317"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16923606"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "A&#46;I&#46; Caplan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jor.1100090504"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Orthop Res&#46;"
                        "fecha" => "1991"
                        "volumen" => "9"
                        "paginaInicial" => "641"
                        "paginaFinal" => "650"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1870029"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Immunological properties of umbilical cord blood-derived mesenchymal stromal cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "W&#46; Oh"
                            1 => "D&#46;S&#46; Kim"
                            2 => "Y&#46;S&#46; Yang"
                            3 => "J&#46;K&#46; Lee"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.cellimm.2008.04.003"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cell Immunol&#46;"
                        "fecha" => "2008"
                        "volumen" => "251"
                        "paginaInicial" => "116"
                        "paginaFinal" => "123"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cells as a cornerstone in a galaxy of intercellular signals&#58; basis for a new era of medicine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "S&#46; Fern&#225;ndez-Francos"
                            1 => "N&#46; Eiro"
                            2 => "L&#46;A&#46; Costa"
                            3 => "S&#46; Escudero-Cernuda"
                            4 => "M&#46;L&#46; Fern&#225;ndez-S&#225;nchez"
                            5 => "F&#46;J&#46; Vizoso"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms22073576"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Mol Sci&#46;"
                        "fecha" => "2021"
                        "volumen" => "22"
                        "paginaInicial" => "3576"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33808241"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reciprocal regulation of mesenchymal stem cells and immune responses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "Y&#46; Wang"
                            1 => "J&#46; Fang"
                            2 => "B&#46; Liu"
                            3 => "C&#46; Shao"
                            4 => "Y&#46; Shi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.stem.2022.10.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Stem Cell&#46;"
                        "fecha" => "2022"
                        "volumen" => "29"
                        "paginaInicial" => "1515"
                        "paginaFinal" => "1530"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/36332569"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anatomic demarcation by positional variation in fibroblast gene expression programs"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "J&#46;L&#46; Rinn"
                            1 => "C&#46; Bondre"
                            2 => "H&#46;B&#46; Gladstone"
                            3 => "P&#46;O&#46; Brown"
                            4 => "H&#46;Y&#46; Chang"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1371/journal.pgen.0020119"
                      "Revista" => array:4 [
                        "tituloSerie" => "PLoS Genet&#46;"
                        "fecha" => "2006"
                        "volumen" => "2"
                        "paginaInicial" => "e119"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Driscoll"
                            1 => "T&#46; Patel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00535-019-01599-1"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Gastroenterol&#46;"
                        "fecha" => "2019"
                        "volumen" => "54"
                        "paginaInicial" => "763"
                        "paginaFinal" => "773"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31270691"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Characterization of secretomes provides evidence for adipose-derived mesenchymal stromal cells subtypes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "N&#46; Kalinina"
                            1 => "D&#46; Kharlampieva"
                            2 => "M&#46; Loguinova"
                            3 => "I&#46; Butenko"
                            4 => "O&#46; Pobeguts"
                            5 => "A&#46; Efimenko"
                          ]
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                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13287-015-0209-8"
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                        "tituloSerie" => "Stem Cell Res Ther&#46;"
                        "fecha" => "2015"
                        "volumen" => "6"
                        "paginaInicial" => "221"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26560317"
                            "web" => "Medline"
                          ]
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                ]
              ]
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            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pluripotent-derived mesenchymal stem&#47;stromal cells&#58; an overview of the derivation protocol efficacies and the differences among the derived cells"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "B&#46;M&#46; de Matos"
                            1 => "A&#46;W&#46; Robert"
                            2 => "M&#46;A&#46; Stimamiglio"
                            3 => "A&#46; Correa"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12015-021-10258-z"
                      "Revista" => array:6 [
                        "tituloSerie" => "Stem Cell Rev Rep&#46;"
                        "fecha" => "2022"
                        "volumen" => "18"
                        "paginaInicial" => "94"
                        "paginaFinal" => "125"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/34545529"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Resolution of psoriasis after allogeneic bone marrow transplantation for chronic myelogenous leukemia&#58; late complications of therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "D&#46;R&#46; Adkins"
                            1 => "M&#46;H&#46; Abidi"
                            2 => "R&#46;A&#46; Brown"
                            3 => "H&#46; Khoury"
                            4 => "L&#46;T&#46; Goodnough"
                            5 => "R&#46; Vij"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.bmt.1702703"
                      "Revista" => array:6 [
                        "tituloSerie" => "Bone Marrow Transplant&#46;"
                        "fecha" => "2000"
                        "volumen" => "26"
                        "paginaInicial" => "1239"
                        "paginaFinal" => "1241"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11149740"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cells in homeostasis and systemic diseases&#58; hypothesis&#44; evidences&#44; and therapeutic opportunities"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "F&#46;J&#46; Vizoso"
                            1 => "N&#46; Eiro"
                            2 => "L&#46; Costa"
                            3 => "P&#46; Esparza"
                            4 => "M&#46; Landin"
                            5 => "P&#46; Diaz-Rodriguez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms20153738"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Mol Sci&#46;"
                        "fecha" => "2019"
                        "volumen" => "20"
                        "paginaInicial" => "3738"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31370159"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cells&#58; a new strategy for immunosuppression and tissue repair"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Shi"
                            1 => "G&#46; Hu"
                            2 => "J&#46; Su"
                            3 => "W&#46; Li"
                            4 => "Q&#46; Chen"
                            5 => "P&#46; Shou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/cr.2010.44"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Res&#46;"
                        "fecha" => "2010"
                        "volumen" => "20"
                        "paginaInicial" => "510"
                        "paginaFinal" => "518"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20368733"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Endometrial regenerative cells&#58; a novel stem cell population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "X&#46; Meng"
                            1 => "T&#46;E&#46; Ichim"
                            2 => "J&#46; Zhong"
                            3 => "A&#46; Rogers"
                            4 => "Z&#46; Yin"
                            5 => "J&#46; Jackson"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/1479-5876-5-57"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Transl Med&#46;"
                        "fecha" => "2007"
                        "volumen" => "5"
                        "paginaInicial" => "57"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18005405"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Functional heterogeneity of mesenchymal stem cells from natural niches to culture conditions&#58; implications for further clinical uses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46;A&#46; Costa"
                            1 => "N&#46; Eiro"
                            2 => "M&#46; Fraile"
                            3 => "L&#46;O&#46; Gonzalez"
                            4 => "J&#46; Sa&#225;"
                            5 => "P&#46; Garcia-Portabella"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00018-020-03600-0"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Mol Life Sci&#46;"
                        "fecha" => "2021"
                        "volumen" => "78"
                        "paginaInicial" => "447"
                        "paginaFinal" => "467"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/32699947"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46;M&#46; Horwitz"
                            1 => "D&#46;J&#46; Prockop"
                            2 => "L&#46;A&#46; Fitzpatrick"
                            3 => "W&#46;W&#46; Koo"
                            4 => "P&#46;L&#46; Gordon"
                            5 => "M&#46; Neel"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/6529"
                      "Revista" => array:6 [
                        "tituloSerie" => "Nat Med&#46;"
                        "fecha" => "1999"
                        "volumen" => "5"
                        "paginaInicial" => "309"
                        "paginaFinal" => "313"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10086387"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cells for treatment of steroid-resistant&#44; severe&#44; acute graft-versus-host disease&#58; a phase II study"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Le Blanc"
                            1 => "F&#46; Frassoni"
                            2 => "L&#46; Ball"
                            3 => "F&#46; Locatelli"
                            4 => "H&#46; Roelofs"
                            5 => "I&#46; Lewis"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0140-6736(08)60690-x"
                      "Revista" => array:6 [
                        "tituloSerie" => "Lancet&#46;"
                        "fecha" => "2008"
                        "volumen" => "371"
                        "paginaInicial" => "1579"
                        "paginaFinal" => "1586"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/18468541"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MEsenchymal StEm cells for Multiple Sclerosis &#40;MESEMS&#41;&#58; a randomized&#44; double blind&#44; cross-over phase I&#47;II clinical trial with autologous mesenchymal stem cells for the therapy of multiple sclerosis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Uccelli"
                            1 => "A&#46; Laroni"
                            2 => "L&#46; Brundin"
                            3 => "M&#46; Clanet"
                            4 => "O&#46; Fernandez"
                            5 => "S&#46;M&#46; Nabavi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13063-019-3346-z"
                      "Revista" => array:5 [
                        "tituloSerie" => "Trials&#46;"
                        "fecha" => "2019"
                        "volumen" => "20"
                        "paginaInicial" => "263"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31072380"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "From the lab to patients&#58; a systematic review and meta-analysis of mesenchymal stem cell therapy for stroke"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;M&#46; Lalu"
                            1 => "J&#46; Montroy"
                            2 => "D&#46; Dowlatshahi"
                            3 => "B&#46; Hutton"
                            4 => "P&#46; Juneau"
                            5 => "N&#46; Wesch"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s12975-019-00736-5"
                      "Revista" => array:6 [
                        "tituloSerie" => "Transl Stroke Res&#46;"
                        "fecha" => "2020"
                        "volumen" => "11"
                        "paginaInicial" => "345"
                        "paginaFinal" => "364"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31654281"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Improved outcomes after mesenchymal stem cells injections for knee osteoarthritis&#58; results at 12-months follow-up&#58; a systematic review of the literature"
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                        0 => array:2 [
                          "etal" => true
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                            1 => "B&#46; Rath"
                            2 => "G&#46; Colarossi"
                            3 => "A&#46; Driessen"
                            4 => "M&#46; Tingart"
                            5 => "M&#46; Niewiera"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00402-019-03267-8"
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                        "tituloSerie" => "Arch Orthop Trauma Surg&#46;"
                        "fecha" => "2020"
                        "volumen" => "140"
                        "paginaInicial" => "853"
                        "paginaFinal" => "868"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/31456015"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human adipose stem cell-derived extracellular nanovesicles for treatment of chronic liver fibrosis"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "H&#46;S&#46; Han"
                            1 => "H&#46; Lee"
                            2 => "D&#46; You"
                            3 => "V&#46;Q&#46; Nguyen"
                            4 => "D&#46;G&#46; Song"
                            5 => "B&#46;H&#46; Oh"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.jconrel.2020.01.042"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Control Release&#46;"
                        "fecha" => "2020"
                        "volumen" => "320"
                        "paginaInicial" => "328"
                        "paginaFinal" => "336"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enhancement of functionality and therapeutic efficacy of cell-based therapy using mesenchymal stem cells for cardiovascular disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "C&#46;W&#46; Yun"
                            1 => "S&#46;H&#46; Lee"
                          ]
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                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms20040982"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Mol Sci&#46;"
                        "fecha" => "2019"
                        "volumen" => "20"
                        "paginaInicial" => "982"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/30813471"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A phase I clinical trial of the treatment of Crohn&#8217;s fistula by adipose mesenchymal stem cell transplantation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "D&#46; Garc&#237;a-Olmo"
                            1 => "M&#46; Garc&#237;a-Arranz"
                            2 => "D&#46; Herreros"
                            3 => "I&#46; Pascual"
                            4 => "C&#46; Peiro"
                            5 => "J&#46;A&#46; Rodr&#237;guez-Montes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s10350-005-0052-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dis Colon Rectum&#46;"
                        "fecha" => "2005"
                        "volumen" => "48"
                        "paginaInicial" => "1416"
                        "paginaFinal" => "1423"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15933795"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Expanded allogeneic adipose-derived mesenchymal stem cells &#40;Cx601&#41; for complex perianal fistulas in Crohn&#8217;s disease&#58; a phase 3 randomised&#44; double-blind controlled trial"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46; Pan&#233;s"
                            1 => "D&#46; Garc&#237;a-Olmo"
                            2 => "G&#46; Van Assche"
                            3 => "J&#46;F&#46; Colombel"
                            4 => "W&#46; Reinisch"
                            5 => "D&#46;C&#46; Baumgart"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/s0140-6736(16)31203-x"
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                        "tituloSerie" => "Lancet&#46;"
                        "fecha" => "2016"
                        "volumen" => "388"
                        "paginaInicial" => "1281"
                        "paginaFinal" => "1290"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cell secretome&#58; toward cell-free therapeutic strategies in regenerative medicine"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "F&#46;J&#46; Vizoso"
                            1 => "N&#46; Eiro"
                            2 => "S&#46; Cid"
                            3 => "J&#46; Schneider"
                            4 => "R&#46; Perez-Fern&#225;ndez"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms18091852"
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                        "tituloSerie" => "Int J Mol Sci&#46;"
                        "fecha" => "2017"
                        "volumen" => "18"
                        "paginaInicial" => "1852"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28841158"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Usage of human mesenchymal stem cells in cell-based therapy&#58; advantages and disadvantages"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46;J&#46; Kim"
                            1 => "J&#46;S&#46; Park"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.12717/dr.2017.21.1.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Dev Reprod&#46;"
                        "fecha" => "2017"
                        "volumen" => "21"
                        "paginaInicial" => "1"
                        "paginaFinal" => "10"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28484739"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Challenges and advances in clinical applications of mesenchymal stromal cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "T&#46; Zhou"
                            1 => "Z&#46; Yuan"
                            2 => "J&#46; Weng"
                            3 => "D&#46; Pei"
                            4 => "X&#46; Du"
                            5 => "C&#46; He"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13045-021-01037-x"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Hematol Oncol&#46;"
                        "fecha" => "2021"
                        "volumen" => "14"
                        "paginaInicial" => "24"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/33579329"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Relative roles of direct regeneration versus paracrine effects of human cardiosphere-derived cells transplanted into infarcted mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "I&#46; Chimenti"
                            1 => "R&#46;R&#46; Smith"
                            2 => "T&#46;S&#46; Li"
                            3 => "G&#46; Gerstenblith"
                            4 => "E&#46; Messina"
                            5 => "A&#46; Giacomello"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1161/circresaha.109.210682"
                      "Revista" => array:6 [
                        "tituloSerie" => "Circ Res&#46;"
                        "fecha" => "2010"
                        "volumen" => "106"
                        "paginaInicial" => "971"
                        "paginaFinal" => "980"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20110532"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human mesenchymal stem cell-conditioned medium improves cardiac function following myocardial infarction"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "L&#46; Timmers"
                            1 => "S&#46;K&#46; Lim"
                            2 => "I&#46;E&#46; Hoefer"
                            3 => "F&#46; Arslan"
                            4 => "R&#46;C&#46; Lai"
                            5 => "A&#46;A&#46;M&#46; van Oorschot"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.scr.2011.01.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Stem Cell Res&#46;"
                        "fecha" => "2011"
                        "volumen" => "6"
                        "paginaInicial" => "206"
                        "paginaFinal" => "214"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/21419744"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stromal cells&#46; Biology of adult mesenchymal stem cells&#58; regulation of niche&#44; self-renewal and differentiation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "C&#46;M&#46; Kolf"
                            1 => "E&#46; Cho"
                            2 => "R&#46;S&#46; Tuan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/ar2116"
                      "Revista" => array:4 [
                        "tituloSerie" => "Arthritis Res Ther&#46;"
                        "fecha" => "2007"
                        "volumen" => "9"
                        "paginaInicial" => "204"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of molecular profiles of human mesenchymal stem cells derived from bone marrow&#44; umbilical cord blood&#44; placenta and adipose tissue"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;S&#46; Heo"
                            1 => "Y&#46; Choi"
                            2 => "H&#46;S&#46; Kim"
                            3 => "H&#46;O&#46; Kim"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3892/ijmm.2015.2413"
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Mol Med&#46;"
                        "fecha" => "2016"
                        "volumen" => "37"
                        "paginaInicial" => "115"
                        "paginaFinal" => "125"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/26719857"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cells are short-lived and do not migrate beyond the lungs after intravenous infusion"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Eggenhofer"
                            1 => "V&#46; Benseler"
                            2 => "A&#46; Kroemer"
                            3 => "F&#46;C&#46; Popp"
                            4 => "E&#46;K&#46; Geissler"
                            5 => "H&#46;J&#46; Schlitt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fimmu.2012.00297"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Immunol&#46;"
                        "fecha" => "2012"
                        "volumen" => "3"
                        "paginaInicial" => "297"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/23056000"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Minimal information for studies of extracellular vesicles 2018 &#40;MISEV2018&#41;&#58; a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "C&#46; Th&#233;ry"
                            1 => "K&#46;W&#46; Witwer"
                            2 => "E&#46; Aikawa"
                            3 => "M&#46;J&#46; Alcaraz"
                            4 => "J&#46;D&#46; Anderson"
                            5 => "R&#46; Andriantsitohaina"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1080/20013078.2018.1535750"
                      "Revista" => array:3 [
                        "tituloSerie" => "J Extracell Vesicles&#46;"
                        "fecha" => "2018"
                        "volumen" => "7"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cell-derived exosomes as a new therapeutic strategy for liver diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "G&#46; Lou"
                            1 => "Z&#46; Chen"
                            2 => "M&#46; Zheng"
                            3 => "Y&#46; Liu"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/emm.2017.63"
                      "Revista" => array:5 [
                        "tituloSerie" => "Exp Mol Med&#46;"
                        "fecha" => "2017"
                        "volumen" => "49"
                        "paginaInicial" => "e346"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/28620221"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exosome mimetics&#58; a novel class of drug delivery systems"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46;A&#46;A&#46; Kooijmans"
                            1 => "P&#46; Vader"
                            2 => "S&#46;M&#46; van Dommelen"
                            3 => "W&#46;W&#46; van Solinge"
                            4 => "R&#46;M&#46; Schiffelers"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2147/ijn.S29661"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Nanomedicine&#46;"
                        "fecha" => "2012"
                        "volumen" => "7"
                        "paginaInicial" => "1525"
                        "paginaFinal" => "1541"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal stem cell-derived exosomes and other extracellular vesicles as new remedies in the therapy of inflammatory diseases"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/cells8121605"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cells&#46;"
                        "fecha" => "2019"
                        "volumen" => "8"
                        "paginaInicial" => "1605"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Treatment of brain inflammatory diseases by delivering exosome encapsulated anti-inflammatory drugs from the nasal region to the brain"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/mt.2011.164"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Ther&#46;"
                        "fecha" => "2011"
                        "volumen" => "19"
                        "paginaInicial" => "1769"
                        "paginaFinal" => "1779"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Potential therapeutic effect of the secretome from human uterine cervical stem cells against both cancer and stromal cells compared with adipose tissue stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.18632/oncotarget.2530"
                      "Revista" => array:6 [
                        "tituloSerie" => "Oncotarget&#46;"
                        "fecha" => "2014"
                        "volumen" => "5"
                        "paginaInicial" => "10692"
                        "paginaFinal" => "10708"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Corneal epithelial wound healing and bactericidal effect of conditioned medium from human uterine cervical stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1167/iovs.14-15859"
                      "Revista" => array:6 [
                        "tituloSerie" => "Invest Ophthalmol Vis Sci&#46;"
                        "fecha" => "2015"
                        "volumen" => "56"
                        "paginaInicial" => "983"
                        "paginaFinal" => "992"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Analysis of patient preferences in lung cancer - estimating acceptable tradeoffs between treatment benefit and side effects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2147/ppa.S235430"
                      "Revista" => array:6 [
                        "tituloSerie" => "Patient Prefer Adherence&#46;"
                        "fecha" => "2020"
                        "volumen" => "14"
                        "paginaInicial" => "927"
                        "paginaFinal" => "937"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Anti-inflammatory effect of conditioned medium from human uterine cervical stem cells in uveitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.exer.2016.06.022"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Eye Res&#46;"
                        "fecha" => "2016"
                        "volumen" => "149"
                        "paginaInicial" => "84"
                        "paginaFinal" => "92"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Tailored hydrogels as delivery platforms for conditioned medium from mesenchymal stem cells in a model of acute colitis in mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/pharmaceutics13081127"
                      "Revista" => array:5 [
                        "tituloSerie" => "Pharmaceutics&#46;"
                        "fecha" => "2021"
                        "volumen" => "13"
                        "paginaInicial" => "1127"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Conditioned medium from human uterine cervical stem cells regulates oxidative stress and angiogenesis of retinal pigment epithelial cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000524484"
                      "Revista" => array:6 [
                        "tituloSerie" => "Ophthalmic Res&#46;"
                        "fecha" => "2022"
                        "volumen" => "65"
                        "paginaInicial" => "556"
                        "paginaFinal" => "565"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human Uterine Cervical Stromal Stem Cells &#40;hUCESCs&#41;&#58; why and how they exert their antitumor activity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Cancer Genomics Proteomics&#46;"
                        "fecha" => "2016"
                        "volumen" => "13"
                        "paginaInicial" => "331"
                        "paginaFinal" => "337"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MSC-based product characterization for clinical trials&#58; an FDA perspective"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.stem.2014.01.013"
                      "Revista" => array:6 [
                        "tituloSerie" => "Cell Stem Cell&#46;"
                        "fecha" => "2014"
                        "volumen" => "14"
                        "paginaInicial" => "141"
                        "paginaFinal" => "145"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The subcutaneous adipose tissue reservoir of functionally active stem cells is reduced in obese patients"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1096/fj.12-207217"
                      "Revista" => array:6 [
                        "tituloSerie" => "FASEB J&#46;"
                        "fecha" => "2012"
                        "volumen" => "26"
                        "paginaInicial" => "4327"
                        "paginaFinal" => "4336"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Donor age negatively affects the immunoregulatory properties of both adipose and bone marrow derived mesenchymal stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.trim.2014.03.001"
                      "Revista" => array:6 [
                        "tituloSerie" => "Transpl Immunol&#46;"
                        "fecha" => "2014"
                        "volumen" => "30"
                        "paginaInicial" => "122"
                        "paginaFinal" => "127"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Age&#44; atherosclerosis and type 2 diabetes reduce human mesenchymal stromal cell-mediated T-cell suppression"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13287-015-0127-9"
                      "Revista" => array:5 [
                        "tituloSerie" => "Stem Cell Res Ther&#46;"
                        "fecha" => "2015"
                        "volumen" => "6"
                        "paginaInicial" => "140"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Aging-related decrease of human ASC angiogenic potential is reversed by hypoxia preconditioning through ROS production"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/mt.2012.213"
                      "Revista" => array:6 [
                        "tituloSerie" => "Mol Ther&#46;"
                        "fecha" => "2013"
                        "volumen" => "21"
                        "paginaInicial" => "399"
                        "paginaFinal" => "408"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Donor variation in the growth properties and osteogenic potential of human marrow stromal cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Cell Biochem&#46;"
                        "fecha" => "1999"
                        "volumen" => "75"
                        "paginaInicial" => "424"
                        "paginaFinal" => "436"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "MSC based therapies&#8211;new perspectives for the injured lung"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/jcm9030682"
                      "Revista" => array:5 [
                        "tituloSerie" => "J Clin Med&#46;"
                        "fecha" => "2020"
                        "volumen" => "9"
                        "paginaInicial" => "682"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Therapeutic potential of products derived from mesenchymal stem&#47;stromal cells in pulmonary disease"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s12931-018-0921-x"
                      "Revista" => array:5 [
                        "tituloSerie" => "Respir Res&#46;"
                        "fecha" => "2018"
                        "volumen" => "19"
                        "paginaInicial" => "218"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hypoxia promotes proliferation and osteogenic differentiation potentials of human mesenchymal stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/jor.21517"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Orthop Res&#46;"
                        "fecha" => "2012"
                        "volumen" => "30"
                        "paginaInicial" => "260"
                        "paginaFinal" => "266"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Impact of low oxygen tension on stemness&#44; proliferation and differentiation potential of human adipose-derived stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.bbrc.2014.04.096"
                      "Revista" => array:6 [
                        "tituloSerie" => "Biochem Biophys Res Commun&#46;"
                        "fecha" => "2014"
                        "volumen" => "448"
                        "paginaInicial" => "218"
                        "paginaFinal" => "224"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Low oxygen tension enhances proliferation and maintains stemness of adipose tissue-derived stromal cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1089/biores.2013.0004"
                      "Revista" => array:5 [
                        "tituloSerie" => "Biores Open Access&#46;"
                        "fecha" => "2013"
                        "volumen" => "2"
                        "paginaInicial" => "199"
                        "paginaFinal" => "205"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effects of hypoxia on in vitro culture of dental-derived stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.archoralbio.2016.03.011"
                      "Revista" => array:6 [
                        "tituloSerie" => "Arch Oral Biol&#46;"
                        "fecha" => "2016"
                        "volumen" => "68"
                        "paginaInicial" => "13"
                        "paginaFinal" => "20"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Spheroid culture of mesenchymal stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1155/2016/9176357"
                      "Revista" => array:3 [
                        "tituloSerie" => "Stem Cells Int&#46;"
                        "fecha" => "2016"
                        "volumen" => "2016"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ischemic preconditioning potentiates the protective effect of mesenchymal stem cells on endotoxin-induced acute lung injury in mice through secretion of exosome"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Int J Clin Exp Med&#46;"
                        "fecha" => "2015"
                        "volumen" => "8"
                        "paginaInicial" => "3825"
                        "paginaFinal" => "3832"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Importance of the origin of mesenchymal &#40;stem&#41; stromal cells in cancer biology&#58; &#8220;alliance&#8221; or &#8220;war&#8221; in intercellular signals"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13578-021-00620-6"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cell Biosci&#46;"
                        "fecha" => "2021"
                        "volumen" => "11"
                        "paginaInicial" => "109"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "IL-10-transduced bone marrow mesenchymal stem cells can attenuate the severity of acute graft-versus-host disease after experimental allogeneic stem cell transplantation"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.bmt.1705644"
                      "Revista" => array:6 [
                        "tituloSerie" => "Bone Marrow Transplant&#46;"
                        "fecha" => "2007"
                        "volumen" => "39"
                        "paginaInicial" => "637"
                        "paginaFinal" => "645"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "In vitro and in vivo immunosuppressive characteristics of hepatocyte growth factor-modified murine mesenchymal stem cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "In Vivo&#46;"
                        "fecha" => "2009"
                        "volumen" => "23"
                        "paginaInicial" => "21"
                        "paginaFinal" => "27"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Enhanced immunosuppressive properties of human mesenchymal stem cells primed by interferon-&#947;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.ebiom.2018.01.002"
                      "Revista" => array:6 [
                        "tituloSerie" => "EBioMedicine&#46;"
                        "fecha" => "2018"
                        "volumen" => "28"
                        "paginaInicial" => "261"
                        "paginaFinal" => "273"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Human bone marrow-derived mesenchymal stem cells in the treatment of gliomas"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1158/0008-5472.Can-04-1874"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cancer Res&#46;"
                        "fecha" => "2005"
                        "volumen" => "65"
                        "paginaInicial" => "3307"
                        "paginaFinal" => "3318"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Non-viral and viral vectors for gene therapy"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Cell Mol Biol &#40;Noisy-le-grand&#41;&#46;"
                        "fecha" => "2005"
                        "volumen" => "51"
                        "paginaInicial" => "3"
                        "paginaFinal" => "22"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Transplantation of CRISPRa system engineered IL10-overexpressing bone marrow-derived mesenchymal stem cells for the treatment of myocardial infarction in diabetic mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1186/s13036-019-0163-6"
                      "Revista" => array:4 [
                        "tituloSerie" => "J Biol Eng&#46;"
                        "fecha" => "2019"
                        "volumen" => "13"
                        "paginaInicial" => "49"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Ocular instillation of conditioned medium from mesenchymal stem cells is effective for dry eye syndrome by improving corneal barrier function"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41598-023-40136-2"
                      "Revista" => array:4 [
                        "tituloSerie" => "Sci Rep&#46;"
                        "fecha" => "2023"
                        "volumen" => "13"
                        "paginaInicial" => "13100"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Conditioned medium of mesenchymal stem cells pretreated with H&#40;2&#41;O&#40;2&#41; promotes intestinal mucosal repair in acute experimental colitis"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/s41598-022-24493-y"
                      "Revista" => array:5 [
                        "tituloSerie" => "Sci Rep&#46;"
                        "fecha" => "2022"
                        "volumen" => "12"
                        "paginaInicial" => "20772"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Corneal regeneration by conditioned medium of human uterine cervical stem cells is mediated by TIMP-1 and TIMP-2"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.exer.2018.12.004"
                      "Revista" => array:6 [
                        "tituloSerie" => "Exp Eye Res&#46;"
                        "fecha" => "2019"
                        "volumen" => "180"
                        "paginaInicial" => "110"
                        "paginaFinal" => "121"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            72 => array:3 [
              "identificador" => "bib0365"
              "etiqueta" => "73"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Mesenchymal &#40;stem&#41; stromal cells based as new therapeutic alternative in inflammatory bowel disease&#58; basic mechanisms&#44; experimental and clinical evidence&#44; and challenges"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/ijms23168905"
                      "Revista" => array:5 [
                        "tituloSerie" => "Int J Mol Sci&#46;"
                        "fecha" => "2022"
                        "volumen" => "23"
                        "paginaInicial" => "8905"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            73 => array:3 [
              "identificador" => "bib0370"
              "etiqueta" => "74"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Antifungal activity of the human uterine cervical stem cells conditioned medium &#40;hUCESC-CM&#41; against candida albicans and other medically relevant species of candida"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fmicb.2018.02818"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Microbiol&#46;"
                        "fecha" => "2018"
                        "volumen" => "9"
                        "paginaInicial" => "2818"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            74 => array:3 [
              "identificador" => "bib0375"
              "etiqueta" => "75"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Exploring the immunomodulatory aspect of mesenchymal stem cells for treatment of severe coronavirus disease 19"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3390/cells11142175"
                      "Revista" => array:5 [
                        "tituloSerie" => "Cells&#46;"
                        "fecha" => "2022"
                        "volumen" => "11"
                        "paginaInicial" => "2175"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            75 => array:3 [
              "identificador" => "bib0380"
              "etiqueta" => "76"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The coronavirus pandemic &#40;SARS-CoV-2&#41;&#58; new problems demand new solutions&#44; the alternative of mesenchymal &#40;stem&#41; stromal cells"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.3389/fcell.2020.00645"
                      "Revista" => array:5 [
                        "tituloSerie" => "Front Cell Dev Biol&#46;"
                        "fecha" => "2020"
                        "volumen" => "8"
                        "paginaInicial" => "645"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
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Journal Information
Vol. 223. Issue 10.
Pages 619-628 (December 2023)
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Vol. 223. Issue 10.
Pages 619-628 (December 2023)
Review
New era of mesenchymal stem cell-based medicine: basis, challenges and prospects
Nueva era de la medicina basada en las células madre mesenquimales: bases, retos y perspectivas
F.J. Vizosoa,b,
Corresponding author
, L.A. Costaa, N. Eiroa,
Corresponding author
noemi.eiro@hospitaldejove.com

Corresponding author.
a Unidad de Investigación, Fundación Hospital de Jove, Gijón, Spain
b Servicio de Cirugía, Fundación Hospital de Jove, Gijón, Spain
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Abstract

Stem cells of mesenchymal origin (MSC) arouse special interest due to their regenerative, anti-inflammatory, anti-apoptotic, anti-oxidative stress, antitumor or antimicrobial properties. However, its implementation in the clinic runs into drawbacks of cell therapy (immunological incompatibility, tumor formation, possible transmission of infections, entry into cellular senescence, difficult evaluation of safety, dose and potency; complex storage conditions, high economic cost or impractical clinical use). Considering that the positive effects of MSC are due, to a large extent, to the paracrine effects mediated by the set of substances they secrete (growth factors, cytokines, chemokines or microvesicles), the in vitro obtaining of these biological products makes possible a medicine cell-free regenerative therapy without the drawbacks of cell therapy. However, this new therapeutic innovation implies challenges, such as the recognition of the biological heterogeneity of MSC and the optimization and standardization of their secretome.

Keywords:
Regenerative medicine
Mesenchymal stem cells
Secretome
Conditioned medium
Exosomes
Resumen

Las células madre de origen mesenquimal (CMM) suscitan un interés especial debido a sus propiedades regenerativas, antiinflamatorias, antiapoptóticas, contra el estrés oxidativo, antitumorales o antimicrobianas. Sin embargo, su implementación en clínica se topa con inconvenientes de la terapia celular como la incompatibilidad inmunológica, la formación de tumores, la posible transmisión de infecciones, la entrada en senescencia celular y la difícil evaluación de seguridad, dosis y potencia; así como complejas condiciones de almacenamiento, elevado coste económico o uso clínico poco práctico. Considerando que los efectos positivos de las CMM se deben, en gran medida, a los efectos paracrinos mediados por el conjunto de sustancias que segregan (factores de crecimiento, citoquinas, quimiocinas o microvesículas), la obtención in vitro de esos productos biológicos posibilita una medicina regenerativa libre de células sin los inconvenientes de la terapia celular. No obstante, esa nueva innovación terapéutica implica retos, como el reconocimiento de la heterogeneidad biológica de las CMM y la optimización y estandarización de su secretoma.

Palabras clave:
Medicina regenerativa
Células madre mesenquimales
Secretoma
Medio condicionado
Exosomas

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