Myocardial Regenerative Therapy: Immunologic Basis for the Potential “Universal Donor Cells”
2008; Elsevier BV; Volume: 86; Issue: 1 Linguagem: Inglês
10.1016/j.athoracsur.2008.03.038
ISSN1552-6259
AutoresRony Atoui, Dominique Shum‐Tim, Ray Chu‐Jeng Chiu,
Tópico(s)Electrospun Nanofibers in Biomedical Applications
ResumoStem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage for which use of autologous donor cells have been preferred to avoid immune rejection. Recently however, rodent, porcine, and even human bone marrow stromal cells have been reported to be uniquely immune tolerant, both in the in vitro mixed lymphocyte co-culture studies and in the in vivo allo-transplant and xeno-transplant models. In this review, we explore the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as "universal donor cells" with fascinating therapeutic implications. Stem cell transplantation is a promising approach for improving cardiac function after severe myocardial damage for which use of autologous donor cells have been preferred to avoid immune rejection. Recently however, rodent, porcine, and even human bone marrow stromal cells have been reported to be uniquely immune tolerant, both in the in vitro mixed lymphocyte co-culture studies and in the in vivo allo-transplant and xeno-transplant models. In this review, we explore the current understanding of the underlying immunologic mechanisms, which can facilitate the use of such cells as "universal donor cells" with fascinating therapeutic implications. A promising approach currently under intensive investigation is stem cell transplantation to improve the function of the injured myocardium through several mechanisms, including myogenesis [1Orlic D. Kajstura T. Chimenti S. Bodine B.M. Leri A. Anversa P. Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 401: 701-705Crossref Scopus (4652) Google Scholar], angiogenesis [2Davani S. Marandin A. Mersin N. et al.Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model.Circulation. 2003; 108II: 253-258Google Scholar], and paracrine effects, which may attenuate left ventricular remodeling [3Dai W. Hale S. Martin B. et al.Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short and long-term effects.Circulation. 2005; 112: 214-223Crossref PubMed Scopus (512) Google Scholar, 4Tang Y. Zhao Q. Qin X. et al.Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction.Ann Thorac Surg. 2005; 80: 229-237Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar]. Since the introduction of this concept in 1992 [5Marelli D. Desrosiers C. El-Alfy M. Kao R.L. Chiu R.C.J. Cell transplantation for myocardial repair: An experimental approach.Cell Transplant. 1992; 1: 383-390PubMed Google Scholar], several experimental models performed on rodents, sheep, dogs, swines, or monkeys have shown that the transplantation of a wide range of stem cells could contribute to the improvement in the cardiac function. Notable among such donor cells are the satellite cells derived from skeletal muscle [6Chiu R.C.J. Zibaitis A. Kao R.L. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation.Ann. Thorac Surg. 1995; 60: 12-18Abstract PubMed Scopus (333) Google Scholar, 7Chachques J.C. Acar C. Herreros J. et al.Cellular cardiomyoplasty: clinical application.Ann Thorac Surg. 2004; 77: 1121-1130Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar], embryonic stem cells [8Hodgson D.M. Behfar A. Zingman L.V. et al.Stable benefit of embryonic stem cell therapy in myocardial infarction.Am J Physiol. 2004; 287: H471-H479Google Scholar], adult marrow stem cells (MSCs) [9Wang J.S. Shum-Tim D. Galipeau J. et al.Marrow stromal cells for cellular cardiomyoplasty: feasibility and clinical advantages.J Thorac Cardiovasc Surg. 2000; 120: 999-1006Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar], adipose stem cells [10Zuk P. Zhu M. Ashjian P. et al.Human adipose tissue is a source of multipotent stem cells.Mol Biol Cell. 2002; 13: 4279-4295Crossref PubMed Scopus (5338) Google Scholar], umbilical cord blood stem cells [11Lee O.K. Kuo T.K. Chen W.M. Lee K.D. Hsieh S.L. Chen T.H. Isolation of multipotent mesenchymal stem cells from umbilical cord blood.Blood. 2004; 103: 1669-1675Crossref PubMed Scopus (1204) Google Scholar], fetal cardiomyocytes, and hematopoietic stem cells (CD34+). The observed beneficial effects of cell transplantation have led to numerous human clinical trials in the past several years [12Schachinger V. Erbs S. Elsasser A. et al.Intracoronary bone-marrow derived progenitor cells in acute myocardial infarction.N Engl J Med. 2006; 355: 1210-1221Crossref PubMed Scopus (1672) Google Scholar]. In this emerging field of cell transplantation, it is generally taken for granted that such donor cells will behave immunologically like any other mature adult cells when transplanted into histocompatibility-mismatched recipients. Thus, the current preferred approach of using autologous stem cells aims to avoid immune rejection of donor cells, which can be expected after allogeneic or xenogeneic transplantation. Despite the promising early results, harvesting autologous cells from individual patients still poses logistic, economic, and timing constraints. Furthermore, most of the patients who could benefit from such therapy are elderly patients with multiple medical comorbidities. Unfortunately, a number of recent studies have documented that MSCs obtained from elderly donors, and those with diabetes, renal failure, or severe ischemic heart disease demonstrated significantly reduced capacity for proliferation, differentiation, and neovascularization, with increased levels of apoptosis in vitro and in vivo [13Heeschen C. Lehmann R. Honold J. et al.Profoundly reduced neovascularization capacity of bone marrow mononuclear cells derived from patients with chronic ischemic heart disease.Circulation. 2004; 109: 1615-1622Crossref PubMed Scopus (569) Google Scholar, 14Stolzing A. Scutt A. Age-related impairment of mesenchymal progenitor cell function.Aging cell. 2006; 1: 1-12Google Scholar]. Such impaired autologous donor cells from sick elderly patients could therefore limit their therapeutic potential. Thus, there would be obvious clinical advantages if "universal donor cells" from healthy young donors could be used for stem cell allo-transplantation without the need for immunosuppressive therapies. In the last several years, increasing experimental findings have pointed toward a unique immunomodulatory property of the MSCs both in the in vitro and in vivo settings [15Nauta A.J. Fibbe W.E. Immunomodulatory properties of mesenchymal stromal cells.Blood. 2007; 110: 3499-3506Crossref PubMed Scopus (1425) Google Scholar]. One intriguing property of MSCs is their ability to escape immune recognition and even actively inhibit immune responses. Although the mechanisms underlying the immunosuppressive effects of MSCs are still not completely understood, their immunosuppressive properties have already been exploited in the clinical setting. The objectives of this review are to critically discuss the evidence behind the role of MSCs in immunomodulation both in vitro and in vivo, and to describe our current understanding of the possible underlying mechanisms by which it occurs. We will also describe their potential clinical use in this context. As previously mentioned, various types of stem cells have been administered to an ischemic myocardium. Studies by several groups have repeatedly documented the successful engraftment of these cells in the adult myocardium, as well as their contribution to the improvement in the overall cardiac function [1Orlic D. Kajstura T. Chimenti S. Bodine B.M. Leri A. Anversa P. Bone marrow cells regenerate infarcted myocardium.Nature. 2001; 401: 701-705Crossref Scopus (4652) Google Scholar, 2Davani S. Marandin A. Mersin N. et al.Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model.Circulation. 2003; 108II: 253-258Google Scholar, 3Dai W. Hale S. Martin B. et al.Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short and long-term effects.Circulation. 2005; 112: 214-223Crossref PubMed Scopus (512) Google Scholar, 4Tang Y. Zhao Q. Qin X. et al.Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction.Ann Thorac Surg. 2005; 80: 229-237Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar, 5Marelli D. Desrosiers C. El-Alfy M. Kao R.L. Chiu R.C.J. Cell transplantation for myocardial repair: An experimental approach.Cell Transplant. 1992; 1: 383-390PubMed Google Scholar, 6Chiu R.C.J. Zibaitis A. Kao R.L. Cellular cardiomyoplasty: myocardial regeneration with satellite cell implantation.Ann. Thorac Surg. 1995; 60: 12-18Abstract PubMed Scopus (333) Google Scholar, 7Chachques J.C. Acar C. Herreros J. et al.Cellular cardiomyoplasty: clinical application.Ann Thorac Surg. 2004; 77: 1121-1130Abstract Full Text Full Text PDF PubMed Scopus (84) Google Scholar, 8Hodgson D.M. Behfar A. Zingman L.V. et al.Stable benefit of embryonic stem cell therapy in myocardial infarction.Am J Physiol. 2004; 287: H471-H479Google Scholar, 9Wang J.S. Shum-Tim D. Galipeau J. et al.Marrow stromal cells for cellular cardiomyoplasty: feasibility and clinical advantages.J Thorac Cardiovasc Surg. 2000; 120: 999-1006Abstract Full Text Full Text PDF PubMed Scopus (396) Google Scholar]. Stem cells are defined as cells capable of self-renewal and pluripotent differentiation into many phenotypes. One clear division in the stem cell family is between those found in the embryo, known as embryonic stem cells, and those found in adult somatic tissue, known as adult stem cells. Embryonic stem cells are derived from the inner cell mass of pre-implantation embryos, and they are able to differentiate into tissue types from all three germ layers. Several issues hinder their clinical application, such as the associated ethical controversies, insufficient availability, and unpredictable electrical behavior, as well as the risk of tumor formation [8Hodgson D.M. Behfar A. Zingman L.V. et al.Stable benefit of embryonic stem cell therapy in myocardial infarction.Am J Physiol. 2004; 287: H471-H479Google Scholar]. Also known as somatic stem cells, the first adult stem cells to be identified were the hematopoietic stem cells in the bone marrow, and most of our earlier knowledge regarding stem cells had been derived from studies of this cell population. Bone MSCs, also called stromal stem cells, marrow progenitor cells, marrow mononuclear cells, mesenchymal stem cells, or marrow-derived adult stem cells represent essentially a population of nonhematopoietic progenitor cells, which can be found in the bone marrow stroma and were previously believed to play only supportive roles for hematopoiesis. Cohnheim [16Cohnheim J. Ueber entzündung und eiterung.Arch Path Anato Physiol Klin Med. 1867; 40: 1Google Scholar], in the 19th century, first suggested the presence of these cells in the blood and their possible role in wound repair [16Cohnheim J. Ueber entzündung und eiterung.Arch Path Anato Physiol Klin Med. 1867; 40: 1Google Scholar]. Friedenstein and colleagues [17Friedenstein A.J. Petrakova K.V. Kurolesova A.I. Frolova G.P. Heterotopic of bone marrow Analysis of precursor cells for osteogenic and hematopoietic tissues.Transplantation. 1968; 6: 230-247Crossref PubMed Scopus (1611) Google Scholar] were the first in the early 1970s to better describe them in a number of species, including mice, rats, rabbits, guinea pigs, hamsters, and humans, showing their differentiation potential into cells of mesenchymal lineage including chondrocytes, osteoblasts, myocytes, and adipocytes. Isolation of MSCs was then undertaken by Caplan [18Caplan A.I. Adult mesenchymal stem cells for tissue engineering versus regenerative medicine.J. Cell Physiol. 2007; 213: 341-347Crossref PubMed Scopus (1504) Google Scholar] who described a technique still used today by harvesting the cells that adhered to the bottom of the plates when the bone marrow cells are cultured in vitro. Marrow stem cells have also been successfully isolated from various mid-gestational fetal tissue, including umbilical cord blood [11Lee O.K. Kuo T.K. Chen W.M. Lee K.D. Hsieh S.L. Chen T.H. Isolation of multipotent mesenchymal stem cells from umbilical cord blood.Blood. 2004; 103: 1669-1675Crossref PubMed Scopus (1204) Google Scholar], amniotic fluid [19De Coppi P. Bartasch G. Siddiqui M.M. et al.Isolation of amniotic stem cell lines with potential for therapy.Nat Biotechnol. 2007; 25: 100-106Crossref PubMed Scopus (1502) Google Scholar], first-trimester and second-trimester fetal tissues [20In't Anker P.S. Noort W.A. Scherjon S.A. et al.Mesenchymal stem cells in human second-trimester bone marrow, liver, lung and spleen exhibit a similar immunophenotype but a heterogeneous multilineage differentiation potential.Haematologica. 2003; 88: 845-852PubMed Google Scholar], as well as umbilical cord mesenchyme [21Yen B.L. Huang H.I. Chien C.C. et al.Isolation of multipotent cells from human term placenta.Stem Cells. 2005; 23: 3-9Crossref PubMed Scopus (400) Google Scholar]. Several in vivo and in vitro studies have confirmed the pluripotent potential of these cells, and have observed the presence of injected MSCs in host adipose tissue, lung, cartilage, central nervous system, liver, spleen, thymus, and skeletal muscle [22Pittenger M.F. MacKay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (17647) Google Scholar, 23Dezawa M. Ishikawa H. Itokazu Y. et al.Bone marrow stromal cells generate muscle cells and repair muscle degeneration.Science. 2005; 309: 314-317Crossref PubMed Scopus (512) Google Scholar]. Although the extent of their plasticity is still under investigation, studies within the last few years have demonstrated the capacity of these MSCs to differentiate into cells of lineages other than mesenchymal, such as hepatocytes, renal cells, and even early astrocytes [24Brazelton T.R. Rossi F.M. Keshet G.I. et al.From marrow to brain: expression of neuronal phenotypes in adult mice.Science. 2000; 290: 1775-1779Crossref PubMed Scopus (1576) Google Scholar]. Because these cells do not have the ethical or tumorigenicity problems of embryonic stem cells, their plasticity have generated much excitement, giving hope to their therapeutic use in a wide range of diseases. Besides the bone marrow, several sources of adult stem cells are known. Zuk and colleagues [10Zuk P. Zhu M. Ashjian P. et al.Human adipose tissue is a source of multipotent stem cells.Mol Biol Cell. 2002; 13: 4279-4295Crossref PubMed Scopus (5338) Google Scholar] have demonstrated that adipose tissue contains both hematopoietic stem cells and MSCs. Peripheral blood is also a source of hematopoietic stem cells and endothelial progenitor cells that have been used for cellular transplantation [12Schachinger V. Erbs S. Elsasser A. et al.Intracoronary bone-marrow derived progenitor cells in acute myocardial infarction.N Engl J Med. 2006; 355: 1210-1221Crossref PubMed Scopus (1672) Google Scholar]. Skeletal myoblasts have been isolated from adult muscle and expanded in culture. In 1992, Marelli and associates [5Marelli D. Desrosiers C. El-Alfy M. Kao R.L. Chiu R.C.J. Cell transplantation for myocardial repair: An experimental approach.Cell Transplant. 1992; 1: 383-390PubMed Google Scholar] reported the first cellular cardiomyoplasty by injecting satellite cells into the injured myocardium, which led to the first clinical trial by Menasche and colleagues in 2001 [25Menasche P. Hagege A.A. Vilquin J.T. et al.Autologous skeletal myoblast transplantation for severe postinfarction left ventricular dysfunction.J Am Coll Cardiol. 2003; 41: 1078-1083Abstract Full Text Full Text PDF PubMed Scopus (1009) Google Scholar]. Recently there has been an explosive advance in our knowledge of adult stem cells for their use as donor cells for regenerative therapies. Associated with such advances are some unexpected and controversial findings that defy current scientific dogmas. One such dilemma is a series of observations indicating that MSCs are immunoprivileged, able to survive, and differentiate in immunocompatibilty-mismatched allogeneic or even xenogeneic transplant recipients [15Nauta A.J. Fibbe W.E. Immunomodulatory properties of mesenchymal stromal cells.Blood. 2007; 110: 3499-3506Crossref PubMed Scopus (1425) Google Scholar]. Such findings challenge the traditional paradigm of immunological recognition concept initially promulgated by Billingham and Medawar [26Billingham R.E. Medawar P.B. The technique of free skin grafting in mammals.J Exp Biol. 1951; 28: 385-402Google Scholar] half a century ago. Although there is continuous controversy surrounding the exact composition of major histocompatibility (MHC) markers on MSCs, most studies describe MSCs as MHC class I positive and MHC class II negative [22Pittenger M.F. MacKay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (17647) Google Scholar]. The expression of class I MHC is important because it protects these cells from natural killer (NK) cell-mediated deletion. As MHC class II proteins are potent allo-antigens, their lack of expression on MSCs allows them to escape recognition by effector CD4+ T-cells. In addition to this, MSCs do not seem to express Fas-ligand nor co-stimulatory molecules, such as B7-1, B7-2, or CD-40 for effector T-cell induction [22Pittenger M.F. MacKay A.M. Beck S.C. et al.Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147Crossref PubMed Scopus (17647) Google Scholar]. The presence of these cell surface markers, along with the findings that MSCs are customary residents of the bone marrow stroma, suggest that MSCs are hypo-immunogenic cells that may play an important role in the immunoregulation provided by the bone marrow microenvironment by evading the recognition of alloreactive cells [27Ryan J. Barry F. Murphy J. Mahon B. Mesenchymal stem cells avoid allogeneic rejection.J of Inflammation. 2005; 2: 1-11Crossref Scopus (48) Google Scholar, 28Rasmusson I. Immune modulation by mesenchymal stem cells.Exp Cell Res. 2006; 312: 2169-2179Crossref PubMed Scopus (296) Google Scholar, 29Le Blanc K. Tammik C. Rosendahl K. Zetterberg E. Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol. 2003; 31: 890-896Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar]. Data supporting the view that MSCs avoid allogeneic response have come from a large body of in vitro experiments involving co-culture mixed lymphocyte reactions [15Nauta A.J. Fibbe W.E. Immunomodulatory properties of mesenchymal stromal cells.Blood. 2007; 110: 3499-3506Crossref PubMed Scopus (1425) Google Scholar, 28Rasmusson I. Immune modulation by mesenchymal stem cells.Exp Cell Res. 2006; 312: 2169-2179Crossref PubMed Scopus (296) Google Scholar, 30Leblanc K. Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med. 2007; 262: 509-525Crossref PubMed Scopus (594) Google Scholar]. Evidence from these studies on human, baboon, and murine MSCs indicate that the use of mismatched MSCs does not provoke a proliferative T-cell response in allogeneic and xenogeneic co-culture studies [29Le Blanc K. Tammik C. Rosendahl K. Zetterberg E. Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol. 2003; 31: 890-896Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar, 31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar, 32Bartholomew A. Sturgeon C. Satskas M. et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol. 2002; 30: 42-48Abstract Full Text Full Text PDF PubMed Scopus (1942) Google Scholar, 33Tse W.T. Pendleton J.D. Beyer W.M. Egalka M.C. Guinan E.C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.Transplantation. 2003; 75: 389-397Crossref PubMed Scopus (1270) Google Scholar]. Increasing data has emerged that MSCs can interact directly with T cells to suppress their alloreactivity in a dose-dependent manner and direct CD4+ T cells to a suppressive phenotype [31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar, 33Tse W.T. Pendleton J.D. Beyer W.M. Egalka M.C. Guinan E.C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.Transplantation. 2003; 75: 389-397Crossref PubMed Scopus (1270) Google Scholar]. Although conflicting results have been reported, such suppression of mixed lymphocyte reactions in vitro seem to arise from both contact-dependent [34Krampera M. Glennie S. Dyson J. et al.Bone marrow mesenchymal stem cells inhibit the response of naïve and memory antigen-specific T cells to their cognate peptide.Blood. 2003; 101: 3722-3729Crossref PubMed Scopus (1367) Google Scholar] and soluble factors [33Tse W.T. Pendleton J.D. Beyer W.M. Egalka M.C. Guinan E.C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.Transplantation. 2003; 75: 389-397Crossref PubMed Scopus (1270) Google Scholar, 35Rasmusson I. Ringden O. Sundberg B. LeBlanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells.Transplantation. 2003; 76: 1208-1213Crossref PubMed Scopus (553) Google Scholar]. However, the exact profile of cytokines produced by MSCs is still provisional and is hindered by lack of standardization in isolation and culture conditions in various studies [27Ryan J. Barry F. Murphy J. Mahon B. Mesenchymal stem cells avoid allogeneic rejection.J of Inflammation. 2005; 2: 1-11Crossref Scopus (48) Google Scholar]. Several studies have shown that MSCs can secrete specific peptides, such as hepatocyte growth factor, which can contribute to the creation of a local immunosuppressive environment [31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar, 36LeBlanc K. Tammik L. Sundberg B. Haynesworth S.E. Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex.Scand J Immunol. 2003; 57: 11-20Crossref PubMed Scopus (1172) Google Scholar]. Similarly, transforming growth factor-β1 is also involved in T-cell suppression by working with hepatocyte growth factor in promoting the allo-escaping phenotype [31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar]. In fact, Di Nicola and colleagues [31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar] showed that neutralizing antibodies to hepatocyte growth factor and transforming growth factor-β1 restored the proliferative response in mixed lymphocyte reactions [31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar]. Other suggested factors include interferon-γ (INF-γ), tumor necrosis factor-α, and interleukin (IL)-2 [30Leblanc K. Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med. 2007; 262: 509-525Crossref PubMed Scopus (594) Google Scholar, 33Tse W.T. Pendleton J.D. Beyer W.M. Egalka M.C. Guinan E.C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.Transplantation. 2003; 75: 389-397Crossref PubMed Scopus (1270) Google Scholar, 36LeBlanc K. Tammik L. Sundberg B. Haynesworth S.E. Ringden O. Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex.Scand J Immunol. 2003; 57: 11-20Crossref PubMed Scopus (1172) Google Scholar]. Interleukin-10 also seems to be constitutively expressed by MSCs and has a well-documented role in T-cell regulation and in the promotion of the suppressor phenotype by antagonizing the action of IL-12 during induction of the inflammatory immune responses [27Ryan J. Barry F. Murphy J. Mahon B. Mesenchymal stem cells avoid allogeneic rejection.J of Inflammation. 2005; 2: 1-11Crossref Scopus (48) Google Scholar]. Furthermore, recent studies have demonstrated the contribution of histocompatibility leukocyte antigen-6 (HLA-6) protein and heme oxygenase-1 in the immunosuppressive effect of rat and human MSCs through various mechanisms, including suppression of T-cell proliferation and inhibition of cytotoxic T-cell activation [37Nasef A. Mathieu N. Chapel A. Immunosuppressive effects of mesenchymal stem cells: involvement of HLA-G.Transplantation. 2007; 84: 231-237Crossref PubMed Scopus (298) Google Scholar, 38Chabannes D. Hill M. Merieau E. A role of heme oxygenase-1 in the immunosuppressive effect of adult rat and human mesenchymal stem cells.Blood. 2007; 110: 3691-3694Crossref PubMed Scopus (283) Google Scholar]. These immunosuppressive properties are retained even when co-stimulatory signals are added to the culture to upregulate the expression of MHC class II [35Rasmusson I. Ringden O. Sundberg B. LeBlanc K. Mesenchymal stem cells inhibit the formation of cytotoxic T lymphocytes, but not activated cytotoxic T lymphocytes or natural killer cells.Transplantation. 2003; 76: 1208-1213Crossref PubMed Scopus (553) Google Scholar], or when T-cells are pre-cultured with INF-γ or re-challenged by the same MSCs [29Le Blanc K. Tammik C. Rosendahl K. Zetterberg E. Ringden O. HLA expression and immunologic properties of differentiated and undifferentiated mesenchymal stem cells.Exp Hematol. 2003; 31: 890-896Abstract Full Text Full Text PDF PubMed Scopus (1360) Google Scholar, 30Leblanc K. Ringden O. Immunomodulation by mesenchymal stem cells and clinical experience.J Intern Med. 2007; 262: 509-525Crossref PubMed Scopus (594) Google Scholar, 31Di Nicola M. Carlo-Stella C. Magni M. et al.Human bone marrow stromal cells suppress T lymphocyte proliferation induced by cellular or non-specific mitogenic stimuli.Blood. 2002; 99: 3838-3843Crossref PubMed Scopus (2613) Google Scholar, 32Bartholomew A. Sturgeon C. Satskas M. et al.Mesenchymal stem cells suppress lymphocyte proliferation in vitro and prolong skin graft survival in vivo.Exp Hematol. 2002; 30: 42-48Abstract Full Text Full Text PDF PubMed Scopus (1942) Google Scholar, 33Tse W.T. Pendleton J.D. Beyer W.M. Egalka M.C. Guinan E.C. Suppression of allogeneic T-cell proliferation by human marrow stromal cells: implications in transplantation.Transplantation. 2003; 75: 389-397Crossref PubMed Scopus (1270) Google Scholar, 39Ryan J.M. Barry F. Murphy J.M. Mahon B.P. Interferon-γ does not break, but promotes the immunosuppressive capacity of adult mesenchymal stem cells.Clinic Exp Immunol. 2007; 149: 353-363Crossref PubMed Scopus (493) Google Scholar]. This indicates that MSCs can preserve their suppressive functions, even within sites of inflammation where inflammatory mediators could upregulate the expression of MHC antigens [28Rasmusson I. Immune modulation by mesenchymal stem cells.Exp Cell Res. 2006; 312: 2169-2179Crossref PubMed Scopus (296) Google Scholar]. One can perhaps speculate that MSCs may play a role in what Chiu called "immunologic homeostasis," because the signaling molecules secreted by these cells are predominantly anti-inflammatory cytokines. When there is tissue injury, such as in acute myocardial infarction, then inflammatory immune cells and cytokines are mobilized at the site of injury. It has been shown that excessive inflammatory response could aggravate the ventricular remodeling process. Mobilization of the MSCs with anti-inflammatory properties may then restore a measure of this immunologic homeostasis by attenuating the inflammatory damage to facilitate the regenerative process, which may be one of the evolutionary roles for these adult stem cells and may be part of the so called paracrine effect as postulated by several investigators [3Dai W. Hale S. Martin B. et al.Allogeneic mesenchymal stem cell transplantation in postinfarcted rat myocardium: short and long-term effects.Circulation. 2005; 112: 214-223Crossref PubMed Scopus (512) Google Scholar, 4Tang Y. Zhao Q. Qin X. et al.Paracrine action enhances the effects of autologous mesenchymal stem cell transplantation on vascular regeneration in rat model of myocardial infarction.Ann Thorac Surg. 2005; 80: 229-237Abstract Full Text Full Text PDF PubMed Scopus (380) Google Scholar]. Of course, this hypothesis is highly sp
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