Received Aug 30; Accepted Nov 5.
Copyright © by the authors. This article has been cited by other articles in PMC. Abstract The need for more effective therapies of chronic and thisis suisse anti aging diseases has led to the attempts of developing more adequate and less invasive treatment methods.
Regenerative medicine relies mainly on the therapeutic potential of stem cells. Mesenchymal stem cells MSCsdue to their immunosuppressive properties and tissue repair abilities, seem to be an ideal tool for cell-based therapies.
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Moreover, some evidence suggests that MSCs are not as immune-privileged as it was previously reported. Importantly, the evidence from the currently completed and ongoing clinical trials demonstrates that allogeneic MSCs transplantation is safe and seems to cause no major side-effects to the patient. Keywords: cell-based therapy, clinical trials, allogeneic, autologous, HLA, HLA-matching, immunomodulation, mesenchymal stem cells 1.
Introduction Regenerative medicine is currently a dynamically growing field of modern medicine. The use of different kinds of stem cells can be viewed as an alternative to organ transplantation and treatment of many diseases such as neurological or cardiovascular diseases [ 12 ] that cannot be effectively treated by conventional methods.
The stem cell based therapies include embryonic ESC [ 3 ] and adult stem cells adult SC with the latter group composed of endothelial progenitor cells EPC [ 4 ], cardiac-derived progenitor cells CDP [ 5 ], cardiac stem cells CSC [ 6 ], and genetically reprogrammed, induced pluripotent stem cells iPSC [ 7 ].
Nonetheless, mesenchymal stem cells MSCs seem to be the most frequently used for this type of therapy. MSCs are relatively easy to isolate and expand in vitro.
Moreover, they secrete cytokines and thisis suisse anti aging factors and have the ability to migrate to the site of an injury where they exert immunomodulatory and regenerative effects [ 8 ]. Among various sources of MSCs, perinatal tissues are of special interest in terms of their use in allogeneic transplantation. Birth-associated tissues including placenta, umbilical cord blood, amniotic fluid and amnion are widely available and can be used for therapeutic purposes [ 91011121314 ].
Additionally, the acquisition of the birth-associated tissues does not require invasive surgery procedures, which becomes an advantage over other tissue sources such as bone marrow or adipose tissue. Although, bone marrow still remains the main source of MSCs for most preclinical and clinical studies [ 151617181920 ], there has been a noticeable shift of interest towards other sources of these cells [ 2122 ].
Numerous studies confirm that MSCs show a tremendous potential in the treatment of many diseases, including immune and non-immune ones. The results of hitherto studies have demonstrated several properties of MSCs that promote their beneficial effects, including, i ability to migrate to the site of injury, ii secretion of soluble factors, iii modulation of immune response, and iv ability to differentiate and transdifferentiate into various cell types.
In vivo studies have revealed that MSCs promote angiogenesis, proliferation, and differentiation of progenitor cells. They also prevent fibrosis and apoptosis, and modulate immune responses [ 23242526 ]. Since tissue injury is always associated with an immune response, MSCs are recruited to a damaged tissue where they secrete a variety of factors including growth factors, cytokines, and chemokines [ 23 ].
Paracrine effect is now recognized as the primary mechanism by which MSCs promote tissue regeneration [ 242728 ].
Other data also suggest that direct cell-to-cell contact and communication through gap junctions may be important in regenerative activity of MSCs [ 29 ]. It is fair to assume that immunological barriers accompanying allogeneic MSCs applications are similar to those governing solid organ and tissue transplantation.
This review focuses on recent discoveries in the field of autologous and allogeneic stem cell transplants with special emphasis on MSCs-based clinical trials not only in the context of therapeutic properties of MSCs, but also of immunological hurdles in allogeneic cell therapies. A better understanding of immunological interactions between the donor cells and the recipient will enable development of safe, effective, and personalized cell therapy based on allogenic MSCs.
Therapeutic Properties of MSCs 2. However, as previously described, class II HLA can be re-expressed under inflammatory circumstances [ 30 ]. In vitro and in vivo experiments and clinical trials showed that MSCs are able to modulate the immune system by suppressing immune responses inhibiting proliferation and maturation of the immune cells [ 30323334 ].
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This mechanism has been described for both autologous and allogeneic MSCs thisis suisse anti aging 31323334 ]. The immunomodulatory effect of MSCs on the immune system can be mediated both through soluble factors and cell—cell interactions [ 35363738 ], however, the paracrine signaling pathways are considered as the key mechanisms by which MSCs influence other cells. In fact, the immunomodulatory properties of MSCs are the sum of microenvironmental conditions of the tissue source that they have been isolated from [ 434445 ].
Interestingly, Yan et al. Moreover, the transplanted MSCs have the ability to transform macrophages from pro-inflammatory M1 to anti-inflammatory M2 phenotype probably via IL [ 4352 ]. Recent studies have shown that macrophages in co-culture with MSCs increased phagocytic activity while the level of secreted thisis suisse anti aging cytokines was decreased [ 53545556575859 ]. Nasef et al. Secreted by MSCs, HLA-G mediates the induction of Treg lymphocyte proliferation [ 6364 ], and may also exert a suppressive effect on allogeneic T cells proliferation.
Secreted G-5 and G-7 isoforms have been shown to have a substantial impact on the allograft acceptance through the MSCs ability to keep the immune tolerance in check [ 6566676869 ]. Secretory Activity of MSCs—Growth Factors and Extracellular Vesicles EVs Mesenchymal stem cells represent a promising treatment approach not only because of their anti-inflammatory and immunomodulatory properties, but also because of their paracrine activity and the secretion of many factors [ 70 ].
The number of factors released by MSCs is remarkable.
For example, secretion of proangiogenic factors such as vascular endothelial growth factor VEGFhepatocyte growth factor HGFand transforming growth factor-β1 TGF-β1 is able to enhance in vivo angiogenesis through the increase of microvascular density thus promoting blood flow recovery in the ischemic tissue [ 277172 ]. Different types of cells release small membrane vesicles, which are referred to as extracellular vesicles EVs [ 73 ].
They represent a modern therapeutic modality, where the cells themselves are not being used directly [ 74 ].
EVs may be carriers of therapeutic properties of MSCs. The interest in EVs is on the rise, especially because of their possible use in clinical settings [ 76 ].
Due to their immunomodulatory, regenerative or anti-cancer properties, EVs represent an intriguing approach in the treatment of cardiovascular, nervous, and immune system diseases. Certainly, the use of EVs might be an alternative to cell-based MSCs therapies, however, more data regarding their safety and therapeutic abilities in various disorders is needed to fully understand their potential [ 747576 ].
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The Essence of an Autologous and Allogeneic Stem Cells Therapies Autologous transplantation involves isolation of own stem cells, which, after proper preparation, are transplanted back into the same patient. In an allogeneic transplantation, stem cells are collected from related or unrelated donors and transplanted into a selected recipient Figure 1.
Mismatches in HLA antigens between the donor and recipient are the most formidable immunological barrier to transplantation and result in serious complications such as engraftment failure, late rejection or graft versus host disease GVHD.