New era of mesenchymal stem cell-based medicine: basis, challenges and prospects

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Additionally, the phenomenon of progressive aging, particularly prevalent in developed countries,<a class="elsevierStyleCrossRef" href="#bib0005">1</a> further complicates the scenario. This aging population will inevitably face physiological vulnerability in the future, encompassing an exponential increase in chronic degenerative diseases (neurodegenerative diseases such as Alzheimer's and Parkinson's; cardiovascular diseases such as myocardial infarction, hypertension, and arteriosclerosis; as well as diabetes, cancer, osteoporosis, or osteoarthritis). This demographic is also more susceptible to severe infections, risks associated with polypharmacy (interaction risks and adverse effects), and, ultimately, a decrease in quality of life.<a class="elsevierStyleCrossRefs" href="#bib0010">2–4</a>The latest studies on “omics” of diseases, such as genomics, transcriptomics, proteomics, or metagenomics, supported by artificial intelligence tools, currently provide only a silhouette of the mechanisms underlying these complex pathophysiological processes. Faced with such complexity, it is evident that targeting therapeutic goals based on limited molecular sequences is not sufficient.Therefore, there is a need for a different approach, and perhaps the time has come to explore new therapeutic alternatives through emerging paradigms in science and medicine. In this context, the development of studies on the archetype of stem cells and regenerative medicine represents one of the greatest endeavors in the history of medical science. Technological and biological advances have raised significant expectations regarding various types of stem cells: embryonic, induced pluripotent stem cells (iPS), and adult stem cells, including hematopoietic, neural, and mesenchymal stem cells (MSCs). Notably, a significant portion of the scientific community has focused on mesenchymal stem cells (MSCs), especially for their exceptional properties (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>).<elsevierMultimedia ident="fig0005"></elsevierMultimedia>Definition and concept of mesenchymal stem cells: from their role in cellular homeostasis to the importance of their dysfunction in systemic diseasesIn the 1950s, Russian hematologist Alexander Friedenstein described a rare population of clonogenic progenitor cells in the mouse bone marrow and other hematopoietic organs that did not belong to the hematopoietic cell lineage.<a class="elsevierStyleCrossRef" href="#bib0025">5</a> These cell populations, resembling fibroblasts, are also known by various terms such as “mesenchymal progenitor cells,” “adult mesenchymal stem cells,” “multipotent stromal cells,” “multipotent stromal cells,” “interstitial stem cells,” “bone marrow stromal cells,” or “medicinal signaling cells”.<a class="elsevierStyleCrossRefs" href="#bib0030">6,7</a> The International Society for Cellular Therapy's Mesenchymal and Tissue Stem Cell Committee established the minimum identification characteristics of human MSCs in 2006: (a) adherence to plastic under standard culture conditions, (b) expression of CD105, CD73, and CD90, and lack of expression of CD45, CD34, CD14 or CD11b, CD79a or CD19, and HLA-DR surface molecules, and (c) the ability to differentiate into osteoblasts, adipocytes, and chondroblasts in vitro.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Additionally, MSCs are considered immunoprivileged cells, as they do not express major histocompatibility complex (MHC) II or co-stimulatory molecules such as CD86, CD40, or CD80.<a class="elsevierStyleCrossRef" href="#bib0040">8</a>Although present in minute quantities in the body, MSCs play a key role in tissue homeostasis through their regenerative, anti-inflammatory, anti-oxidative stress, antimicrobial, antifibrotic, antiapoptotic, or antitumor effects. These positive effects are achieved through the secretion of cytokines, growth factors, and even extracellular vesicles (EVs)<a class="elsevierStyleCrossRefs" href="#bib0045">9–12</a> (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The functional capacity of MSCs may be attributed to their derivation from the mesoderm, a highly functional embryological layer, similar to the immune and circulatory systems. Evidence suggests that the mesoderm evolves to form a stroma intimately interconnected with tissues derived from the ectoderm or endoderm. Although MSCs exhibit perivascular localization in different anatomical locations, their functional capacity to generate paracrine signals varies.<a class="elsevierStyleCrossRef" href="#bib0065">13</a> Therefore, the functional heterogeneity of MSCs appears to reflect their adaptation to interact functionally with the microenvironment of different tissues and organs.<a class="elsevierStyleCrossRefs" href="#bib0055">11,12,14</a>The concept of MSC dysfunction in systemic diseases arose from the observation that patients with autoimmune diseases such as systemic lupus erythematosus (SLE), diabetes mellitus (DM), rheumatoid arthritis (RA), multiple sclerosis, or psoriasis entered remission when treated with allogeneic transplantation of MSCs or hematopoietic stem cells, but not after autologous transplants. Based on these findings, which occurred in the context of leukemia or lymphoma treatment,<a class="elsevierStyleCrossRef" href="#bib0075">15</a> it has been hypothesized that in these cases, the remission of systemic disease occurred due to the “resetting” of immune memory. However, it could also be due to the restoration of internal homeostasis by administering normally functional MSCs from healthy donors. In this sense, it is now becoming evident that depletion or dysfunction of such cells may underlie the pathophysiology of diseases such as SLE, DM, RA, multiple sclerosis, idiopathic pulmonary fibrosis, Parkinson's disease, amyotrophic lateral sclerosis, psoriasis, myelodysplastic syndromes, or premature aging syndromes.<a class="elsevierStyleCrossRef" href="#bib0080">16</a> Moreover, these systemic diseases associated with MSC dysfunction are characterized by the perpetuation of inflammatory states, constant emission of “alarm signals,” proliferation, mobilization, and, ultimately, an endless sequestration of MSCs in damaged tissues, likely leading to depletion of this important type of specialized homeostatic and reparative cells.<a class="elsevierStyleCrossRefs" href="#bib0080">16,17</a>Based on these findings, 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 (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>A). This situation could be due to the exhaustion or depletion of exhausted MSCs (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>B), or their primary or secondary cellular dysfunction induced by alterations in the tissue microenvironment (<a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>C). Thus, considering this new pathophysiological paradigm may serve as the basis for developing new therapeutic alternatives using MSCs or biological products derived from their secretome.<a class="elsevierStyleCrossRef" href="#bib0080">16</a><elsevierMultimedia ident="fig0010"></elsevierMultimedia>Era of mesenchymal stem cell-based cell therapy: expectations, results, and limitationsBone marrow, subcutaneous fat, Wharton's jelly, and umbilical cords are the most commonly used sources of MSCs. However, other origins such as fetal/neonatal tissues, dental pulp, or those of uterine and reproductive origin<a class="elsevierStyleCrossRefs" href="#bib0075">15,18</a> are gaining increasing interest.<a class="elsevierStyleCrossRef" href="#bib0095">19</a>In addition to the classic research and clinical applications of MSCs, such as in osteogenesis imperfecta,<a class="elsevierStyleCrossRef" href="#bib0100">20</a> graft-versus-host disease (GVHD),<a class="elsevierStyleCrossRef" href="#bib0105">21</a> multiple sclerosis,<a class="elsevierStyleCrossRef" href="#bib0110">22</a> strokes,<a class="elsevierStyleCrossRef" href="#bib0115">23</a> osteoarthritis,<a class="elsevierStyleCrossRef" href="#bib0120">24</a> liver cirrhosis,<a class="elsevierStyleCrossRef" href="#bib0125">25</a> cardiovascular disease,<a class="elsevierStyleCrossRef" href="#bib0130">26</a> or Crohn's disease,<a class="elsevierStyleCrossRefs" href="#bib0135">27,28</a> the wide range of possible applications of MSCs and/or their secretome is constantly expanding. As of July 21, 2023, 1315 interventional clinical trials (see ClinicalTrials.gov) have been registered in various indications. However, despite all these positive findings, there are significant limitations, including the use of an invasive isolation method, difficulty in cultivating cells in sufficient quantities, immunological incompatibility, tumor or embolus formation, potential transmission of infections, entry into senescence, difficult evaluation of safety, dosage, and potency, complex storage conditions, high economic costs, impractical clinical use, difficult availability of large quantities for immediate use, and biological heterogeneity of cells in relation to the donor and tissue origin.<a class="elsevierStyleCrossRefs" href="#bib0095">19,29–31</a> All these factors make it challenging for this new type of medicine to be generalized. Therefore, it is necessary to find new strategic alternatives in the context of MSC-based medicine.Possibility of cell-free therapy based on the secretome of mesenchymal stem cellsInitially, the therapeutic effects of MSCs were attributed to their grafting and differentiation capacity. However, it has been subsequently demonstrated that the implantation period of MSCs is usually too short to have an effective impact.<a class="elsevierStyleCrossRefs" href="#bib0160">32,33</a> In fact, less than 1% of MSCs are reported to survive more than a week after systemic administration,<a class="elsevierStyleCrossRef" href="#bib0170">34</a> suggesting that the main effects of MSCs are mediated by paracrine mechanisms through components present in their secretome.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a> The secretome of MSCs can be obtained in vitro under cell culture conditions (referred to as conditioned medium), containing a wide range of soluble bioactive factors (growth factors, cytokines, or chemokines) and extracellular vesicles (EVs). In addition to avoiding the drawbacks of cell therapy, this offers new significant advantages, such as a better evaluation of the product regarding safety, dosage, and potency, similar to conventional therapeutic agents; simpler storage without the need for cryoprotective agents; and a more economical and practical approach for clinical use.<a class="elsevierStyleCrossRef" href="#bib0145">29</a> Furthermore, the importance of a particularly relevant component of the MSC secretome, namely EVs,<a class="elsevierStyleCrossRef" href="#bib0185">37</a> should be emphasized. These microvesicles are surrounded by a membrane and contain a diverse range of components, such as RNA, lipids, and proteins, including cytokines, chemokines, interleukins, integrins, tetraspanins (CD81, CD63, and CD9), transport proteins, signal transduction factors (kinases), cytoskeleton proteins, and metabolic enzymes. EVs are classified based on their origin into exosomes (70–150nm), derived from the endosomal compartment corresponding to the intraluminal vesicles of multivesicular endosomes; microvesicles (100–1000nm), which are budding from the plasma membrane; and apoptotic bodies, larger fragments of apoptotic cells (500–2000nm). Exosomes are less complex and immunogenic than their parent cells, as they have a lower content of membrane-bound proteins.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Moreover, the production and storage of exosomes are easier than for MSCs.<a class="elsevierStyleCrossRef" href="#bib0195">39</a> Other advantages of exosomes include a longer half-life in the bloodstream, the ability to cross the blood-brain barrier, and tropism towards inflamed tissues and tumors.<a class="elsevierStyleCrossRefs" href="#bib0200">40,41</a>In vitro and in vivo studies on the secretomes of MSCs have been rapidly increasing in recent years, demonstrating that these biological products reproduce the effects of their parent cells, suggesting a new therapeutic strategy<a class="elsevierStyleCrossRefs" href="#bib0045">9,29</a> (<a class="elsevierStyleCrossRef" href="#fig0015">Fig. 3</a>).<elsevierMultimedia ident="fig0015"></elsevierMultimedia>New concepts and challenges of a mesenchymal stem cell therapeutic strategy 2.0 based on the products of its secretomeFrom the review of specialized literature, a prospective vision of the evolution of research and potential applications of MSCs in the last two decades can be observed: from purely regenerative interest to their potential anti-inflammatory and other actions such as pro-angiogenic, anti-oxidative stress, anti-microbial, or anti-tumoral; from initially autologous transplantation to allogeneic; and from cell therapy to the possibility of a cell-free therapy based on products derived from its secretome. Likewise, we can anticipate a series of challenges that will need to be addressed to bring this latter proposal to the forefront of patient care: considering the importance of the functional heterogeneity of MSCs, industrial production and standardization of their secretome, 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 2.0.Heterogeneity of mesenchymal stem cellsThe 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. However, this biological reality should rather represent a key strategic opportunity to choose the most appropriate MSC for each therapeutic indication. The functional capacity of MSCs varies depending on their tissue or organ origin, donor characteristics, and the conditions of the artificial niche in culture and expansion.Origin-dependent heterogeneityThe functional heterogeneity of MSCs reflects the diversity of environments present in their natural niches, which differ widely in the dynamics of communication between various cell communities, chemical conditions, and mechanical conditions of their tissue microenvironment.<a class="elsevierStyleCrossRef" href="#bib0170">34</a> Consequently, differences have been reported between MSCs from different origins regarding their proliferation capacity, transdifferentiation, or immunophenotype. This functional heterogeneity of MSCs is also reflected in variations in the production of their secretome, including microvesicles, and therefore, it is something to consider for the various potential therapeutic applications of these biological products. All of this leads us to conceive the importance of new sources of MSCs that, in addition to those traditionally considered, can open up a range of more specific therapeutic possibilities.<a class="elsevierStyleCrossRef" href="#bib0210">42</a> An example of this is the identification by our Group of a new source of MSCs in the human uterine cervix (hUCESC - “human Uterine Cervical Stem Cell”). These cells can be easily obtained by cytology or from hysterectomy specimens. Once extracted, they show a high proliferative rate in culture, allowing them to be obtained in large quantities compared to other types of MSCs. In addition, their secretome, or conditioned medium, obtained under culture conditions, contains substances with regenerative, anti-inflammatory, immunoregulatory, antimicrobial, oxidative stress-reducing, and anticancer properties, more potent than those obtained from MSCs of other origins, such as widely used adipose tissue-derived MSCs.<a class="elsevierStyleCrossRefs" href="#bib0215">43–47</a>The potential presented by hUCESC and its secretome could be related to its origin in the human body. hUCESC is obtained from the uterine cervix, an area that is a gateway to the uterine cavity (“the chest of life”), and is constantly exposed to harmful elements present in the vagina, such as a proinflammatory acidic environment, bacteria and fungi that colonize it, or viruses like human papillomavirus, which plays a prominent role in cancer development.Thus, the existence in this area of cells that possess the ability to produce a cocktail of substances that protect it seems reasonable.<a class="elsevierStyleCrossRef" href="#bib0240">48</a>Donor-dependent heterogeneityIn addition to MSC dysfunction in relation to the existence of systemic diseases, there are other causes of donor-dependent heterogeneity. It is known that when theoretically identical populations of MSCs from different healthy individuals are compared, they can show different properties of the secretome.<a class="elsevierStyleCrossRef" href="#bib0245">49</a> The age and obesity of the donor are determining factors in this regard, especially for MSCs from adipose tissue. Although adipose tissue is considered an important reservoir of stem cells, 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.<a class="elsevierStyleCrossRefs" href="#bib0205">41,50</a>MSCs collected from older donors are characterized by a higher percentage of apoptotic cells and a slower proliferation rate. In addition, 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">51,52</a> compared to MSCs from younger individuals.<a class="elsevierStyleCrossRef" href="#bib0265">53</a> However, even MSCs isolated from young and healthy donors show marked differences in their proliferation rate, differentiation capacity, and clinical utility. For example, 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.<a class="elsevierStyleCrossRef" href="#bib0270">54</a>Production, standardization, and modification of the secretome of mesenchymal stem cellsGiven the undeniable scientific and technological value of the secretome derived from MSCs and its likely high future demand, the need to establish its in vitro production on an industrial scale becomes imperative. Fortunately, we now have the necessary technology, such as bioreactors, 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. These bioengineering systems combine materials that enable high cell culture density, control of hydrodynamic parameters and agitation of the culture medium, as well as precise control of chemical parameters or nutrient gradients<a class="elsevierStyleCrossRefs" href="#bib0145">29,55,56</a> (<a class="elsevierStyleCrossRef" href="#fig0020">Fig. 4</a>). Additionally, there is the possibility of establishing ex vivo conditions that can cause modifications of the MSC secretome oriented towards more specific therapeutic applications, such as O2 concentration, 3D culture systems, pre-conditioning methods, or genetic manipulation.<elsevierMultimedia ident="fig0020"></elsevierMultimedia>Cells are generally cultured in vitro under an O2 tension like that present in our atmosphere (21%). However, several studies have shown that MSCs cultured at low O2 concentrations, which are more representative of tissues, better retain their proliferative capacity, surface antigen expression, and differentiation potential, compared to those cultured at atmospheric O2 tension.<a class="elsevierStyleCrossRefs" href="#bib0045">9,19,57–60</a> Conventional cell culture is generally carried out in a two-dimensional (2D) system where cells grow as monolayers. However, 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, such as increased production of angiogenic factors or anti-cancer proteins.<a class="elsevierStyleCrossRefs" href="#bib0045">9,61–63</a> Moreover, MSCs transfected with anti-inflammatory genes such as IL-10, HGF, IDO, or Foxp3 enhance the anti-inflammatory potency of their secretome.<a class="elsevierStyleCrossRefs" href="#bib0320">64–66</a> Overexpression of BDNF or interferon-beta induces a significantly greater neuroprotective effect than native MSCs and enhances the antitumor effect on glioma cells, respectively.<a class="elsevierStyleCrossRefs" href="#bib0045">9,67</a> Despite positive data on the genetic manipulation of MSCs, there are aspects that limit their clinical application due to safety issues, including potential tumorigenicity, toxicity, and immunogenicity derived from the use of viral agents.<a class="elsevierStyleCrossRef" href="#bib0340">68</a> Therefore, the Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas9 genome editing technology can improve the therapeutic potential of the secretome with greater safety for the patient.<a class="elsevierStyleCrossRef" href="#bib0345">69</a> Specific functional tests, in vitro and/or in vivo, may be of interest to ensure the homogeneity of the action of these products derived from the MSC secretome before clinical applications.New challenges of therapeutic applications of mesenchymal stem cell technology 2.0The availability of such a versatile biological product opens the possibility of a wide range of therapeutic potentialities. There is the possibility of developing formulations adapted for the topical treatment of multifactorial diseases with complex physiopathology, such as dry eye<a class="elsevierStyleCrossRef" href="#bib0350">70</a> syndrome or inflammatory bowel disease.<a class="elsevierStyleCrossRef" href="#bib0355">71</a> In relation to the former, our preclinical results showed that the topical installation of an eye drop based on the conditioned medium of hUCESC (MC-hUCESC) induced potent regenerative and anti-inflammatory effects in the damaged cornea of animals,<a class="elsevierStyleCrossRefs" href="#bib0215">43,45,72</a> as well as in an experimental model of uveitis. Inflammatory bowel diseases, such as ulcerative colitis and Crohn's disease, which are chronic and of unknown etiology, have increased their incidence in the population up to 30 times in recent decades. MSCs are a therapeutic alternative for these processes.<a class="elsevierStyleCrossRef" href="#bib0365">73</a> As demonstrated by our in vivo data in a murine experimental model of colitis, topical application using enemas of a combination of MC-hUCESC with a mucoadhesive hydrogel demonstrated potent anti-inflammatory and regenerative effects. In mice treated with this innovative product, our results not only showed a radical improvement in all histological parameters of colitis (inflammation, ulceration, atrophy, and dysplasia) but also a decrease in the gene expression of inflammatory cytokines, such as TNF-alpha, IL-6, or interferon-gamma, which have been shown to play a very special role in the complex physiopathology of inflammatory bowel disease.<a class="elsevierStyleCrossRef" href="#bib0230">46</a>Cancer continues to experience an unstoppable increase in its incidence, estimated to go from 14 million new cases in 2012 to 19 million in 2025, generating a 50% mortality rate overall. MSCs derived from reproductive tissues, such as the uterus, placenta, or umbilical cord or amniotic fluid, have shown anti-tumor activity against a wide variety of malignant tumors. These effects may be due to highly present soluble elements in their secretomes that induce inhibition of tumor growth,<a class="elsevierStyleCrossRef" href="#bib0315">63</a> but also, in part, to exosomes with a recognized anti-tumor effect. This is especially relevant when considering three fundamental aspects: i) cancer cells internalize a large percentage of exosomes compared to normal cells<a class="elsevierStyleCrossRefs" href="#bib0045">9,63</a>; ii) there is a demonstrated tropism of these microvesicles toward tumors; and iii) the possibility of loading these particles with anti-tumor agents, such as anti-cancer cytokines, oncolytic viruses, or chemotherapeutics.<a class="elsevierStyleCrossRef" href="#bib0315">63</a> In this nanotechnological context, exosomes can represent innovative “Trojan horses” in the conception of a new, sophisticated, and selective anti-tumor strategy.The fight against infections is becoming a real challenge for medicine. According to epidemiologists' estimates, by the year 2030, 13 million deaths worldwide will occur due to antibiotic resistance. Preliminary results demonstrate the bactericidal<a class="elsevierStyleCrossRef" href="#bib0215">43</a> or antifungal activity<a class="elsevierStyleCrossRef" href="#bib0370">74</a> of the MSC secretome. This may be because the MSC secretome contains high concentrations of cytokines with recognized antibacterial<a class="elsevierStyleCrossRef" href="#bib0075">15</a> and antifungal effects.<a class="elsevierStyleCrossRef" href="#bib0370">74</a> Additionally, the MSC secretome may be very useful in trying to counteract the effects of the inflammatory storm caused by viral infection.<a class="elsevierStyleCrossRef" href="#bib0375">75</a> Currently, 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, which at least for now show positive safety data.<a class="elsevierStyleCrossRef" href="#bib0380">76</a> This justifies the extraordinary interest in the development of this new biotechnology for future viral pandemics.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, such as cardiovascular, neurodegenerative, or osteoarticular diseases.<a class="elsevierStyleCrossRef" href="#bib0385">77</a> In this context, we believe that a strategy of restoring the disrupted homeostatic balance through the administration of products secreted by MSCs has a place.<a class="elsevierStyleCrossRef" href="#bib0390">78</a>ConclusionsThe possibility of using products derived from the secretome of MSCs is placed in the context of the current needs of medicine, where the complex pathophysiological reality of diseases renders the classic therapeutic concept of the pharmaceutical industry, “one disease, one therapeutic target,” insufficient. The real answer to this challenge is believed to lie in nature; as Albert Einstein stated, “Look deep into nature, and then you will understand everything better.”MSCs are increasingly recognized as key elements in internal homeostasis through their paracrine effect by producing a cocktail of factors with regenerative, anti-inflammatory, anti-oxidative stress, antimicrobial, or antitumor effects. However, cell therapy based on the transplantation of these cells faces the general disadvantages of cell therapy, which include all the inconveniences of transplanting proliferating live cells. Nevertheless, a 2.0 MSC technology is emerging, representing a disruptive innovation that allows the implementation of a cell-free regenerative medicine. This is based on the availability of a biological derivative like the MSC secretome. This product can be produced in large quantities, formulated specifically for many types of possible therapeutic applications, and serve as the basis for future research and technological developments that represent a source of innovation in medicine. The demanding requirements of regulatory agencies are well known, but there are protocols and procedures that represent reasonable “roadmaps” to progressively bring this technology closer to the interest of therapeutic medicine. The only failure is not to try!" "textoCompletoSecciones" => array:1 [ "secciones" => array:17 [ 0 => array:3 [ "identificador" => "xres2048672" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:2 [ "identificador" => "xpalclavsec1749888" "titulo" => "Keywords" ] 2 => array:3 [ "identificador" => "xres2048673" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 3 => array:2 [ "identificador" => "xpalclavsec1749887" "titulo" => "Palabras clave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:2 [ "identificador" => "sec0010" "titulo" => "Definition and concept of mesenchymal stem cells: from their role in cellular homeostasis to the importance of their dysfunction in systemic diseases" ] 6 => array:2 [ "identificador" => "sec0015" "titulo" => "Era of mesenchymal stem cell-based cell therapy: expectations, results, and limitations" ] 7 => array:2 [ "identificador" => "sec0020" "titulo" => "Possibility of cell-free therapy based on the secretome of mesenchymal stem cells" ] 8 => array:2 [ "identificador" => "sec0025" "titulo" => "New concepts and challenges of a mesenchymal stem cell therapeutic strategy 2.0 based on the products of its secretome" ] 9 => array:2 [ "identificador" => "sec0030" "titulo" => "Heterogeneity of mesenchymal stem cells" ] 10 => array:2 [ "identificador" => "sec0035" "titulo" => "Origin-dependent heterogeneity" ] 11 => array:2 [ "identificador" => "sec0040" "titulo" => "Donor-dependent heterogeneity" ] 12 => array:2 [ "identificador" => "sec0045" "titulo" => "Production, standardization, and modification of the secretome of mesenchymal stem cells" ] 13 => array:2 [ "identificador" => "sec0050" "titulo" => "New challenges of therapeutic applications of mesenchymal stem cell technology 2.0" ] 14 => array:2 [ "identificador" => "sec0055" "titulo" => "Conclusions" ] 15 => array:2 [ "identificador" => "xack713714" "titulo" => "Acknowledgements" ] 16 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2023-09-21" "fechaAceptado" => "2023-10-25" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1749888" "palabras" => array:5 [ 0 => "Regenerative medicine" 1 => "Mesenchymal stem cells" 2 => "Secretome" 3 => "Conditioned medium" 4 => "Exosomes" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1749887" "palabras" => array:5 [ 0 => "Medicina regenerativa" 1 => "Células madre mesenquimales" 2 => "Secretoma" 3 => "Medio condicionado" 4 => "Exosomas" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "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." ] "es" => array:2 [ "titulo" => "Resumen" "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." ] ] "multimedia" => array:4 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1581 "Ancho" => 3341 "Tamanyo" => 287338 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0005" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Mesenchymal stem cells in the context of a galaxy of intercellular signals participating in various physiopathological processes through the secretion of soluble factors and extracellular vesicles." ] ] 1 => array:8 [ "identificador" => "fig0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 710 "Ancho" => 3341 "Tamanyo" => 214813 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0010" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Possible scenarios of intercellular communication between somatic cells and MSCs in the context of tissue homeostasis: (A) Damaged somatic cells could send “alarm signals” indicative of dysfunction to “resident sentinel” MSCs, triggering their proliferation and activation in response to somatic cell damage, ultimately leading to the production of a specialized secretome; (B) Inadequate response to these alarm signals by MSCs due to exhaustion or depletion; and (C) Inadequate response to alarm signals by MSCs due to primary or secondary cellular dysfunction. MSC: Mesenchymal Stem Cells." ] ] 2 => array:8 [ "identificador" => "fig0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 973 "Ancho" => 1675 "Tamanyo" => 64823 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0015" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Evolution of the number of publications based on the secretome and extracellular vesicles of mesenchymal stem cells. Source: PubMed." ] ] 3 => array:8 [ "identificador" => "fig0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1111 "Ancho" => 2925 "Tamanyo" => 253585 ] ] "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at0020" "detalle" => "Figure " "rol" => "short" ] ] "descripcion" => array:1 [ "en" => "Graphic representation of obtaining conditioned medium and microvesicles from mesenchymal stem cells and industrial expansion using bioreactors." ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:78 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:1 [ "referenciaCompleta" => "Vol. no. 430. 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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,

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investigacion@hospitaldejove.com

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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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Mesenchymal stem cells in the context of a galaxy of intercellular signals participating in various physiopathological processes through the secretion of soluble factors and extracellular vesicles&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">It is estimated that around 40&#37; of the global population will experience&#44; at some point in their lives&#44; a disease involving an uncontrollable inflammatory or autoimmune process that is not satisfactorily managed with current pharmacological therapies&#46; Additionally&#44; the phenomenon of progressive aging&#44; particularly prevalent in developed countries&#44;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> further complicates the scenario&#46; This aging population will inevitably face physiological vulnerability in the future&#44; encompassing an exponential increase in chronic degenerative diseases &#40;neurodegenerative diseases such as Alzheimer&#39;s and Parkinson&#39;s&#59; cardiovascular diseases such as myocardial infarction&#44; hypertension&#44; and arteriosclerosis&#59; as well as diabetes&#44; cancer&#44; osteoporosis&#44; or osteoarthritis&#41;&#46; This demographic is also more susceptible to severe infections&#44; risks associated with polypharmacy &#40;interaction risks and adverse effects&#41;&#44; and&#44; ultimately&#44; a decrease in quality of life&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#8211;4</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The latest studies on &#8220;omics&#8221; of diseases&#44; such as genomics&#44; transcriptomics&#44; proteomics&#44; or metagenomics&#44; supported by artificial intelligence tools&#44; currently provide only a silhouette of the mechanisms underlying these complex pathophysiological processes&#46; Faced with such complexity&#44; it is evident that targeting therapeutic goals based on limited molecular sequences is not sufficient&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Therefore&#44; there is a need for a different approach&#44; and perhaps the time has come to explore new therapeutic alternatives through emerging paradigms in science and medicine&#46; In this context&#44; the development of studies on the archetype of stem cells and regenerative medicine represents one of the greatest endeavors in the history of medical science&#46; Technological and biological advances have raised significant expectations regarding various types of stem cells&#58; embryonic&#44; induced pluripotent stem cells &#40;iPS&#41;&#44; and adult stem cells&#44; including hematopoietic&#44; neural&#44; and mesenchymal stem cells &#40;MSCs&#41;&#46; Notably&#44; a significant portion of the scientific community has focused on mesenchymal stem cells &#40;MSCs&#41;&#44; especially for their exceptional properties &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Definition and concept of mesenchymal stem cells&#58; from their role in cellular homeostasis to the importance of their dysfunction in systemic diseases</span><p id="par0020" class="elsevierStylePara elsevierViewall">In the 1950s&#44; Russian hematologist Alexander Friedenstein described a rare population of clonogenic progenitor cells in the mouse bone marrow and other hematopoietic organs that did not belong to the hematopoietic cell lineage&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a> These cell populations&#44; resembling fibroblasts&#44; are also known by various terms such as &#8220;mesenchymal progenitor cells&#44;&#8221; &#8220;adult mesenchymal stem cells&#44;&#8221; &#8220;multipotent stromal cells&#44;&#8221; &#8220;multipotent stromal cells&#44;&#8221; &#8220;interstitial stem cells&#44;&#8221; &#8220;bone marrow stromal cells&#44;&#8221; or &#8220;medicinal signaling cells&#8221;&#46;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#44;7</span></a> The International Society for Cellular Therapy&#39;s Mesenchymal and Tissue Stem Cell Committee established the minimum identification characteristics of human MSCs in 2006&#58; &#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" => "Possibility of cell-free therapy based on the secretome of mesenchymal stem cells"
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          "titulo" => "Heterogeneity of mesenchymal stem cells"
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          "titulo" => "Production&#44; standardization&#44; and modification of the secretome of mesenchymal stem cells"
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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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Article information

ISSN: 22548874
Original language: English

DOI:10.1016/j.rceng.2023.11.002

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