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Division of Cardiac Surgery, McGill University Health Center, Montreal, Quebec, Canada
* Address correspondence to Dr Chiu, The Montreal General Hospital, MUHC, Suite C9-169, 1650 Cedar Ave, Montreal, Quebec, H3G 1A4, Canada (Email: ray.chiu{at}mcgill.ca).
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Abstract |
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 Top Abstract IntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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Introduction |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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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 [13, 14]. 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 [15]. 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.
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The Proliferating Sources of Stem Cells |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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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 [8].
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 [16], in the 19th century, first suggested the presence of these cells in the blood and their possible role in wound repair [16]. Friedenstein and colleagues [17] 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 [18] 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 [11], amniotic fluid [19], first-trimester and second-trimester fetal tissues [20], as well as umbilical cord mesenchyme [21]. 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 [22, 23]. 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 [24]. 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 [10] 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 [12]. Skeletal myoblasts have been isolated from adult muscle and expanded in culture. In 1992, Marelli and associates [5] 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 [25].
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MSCs and Their Immunotolerant Properties |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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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 [22]. 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 [22]. 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 [27–29].
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Immunomodulatory Role of MSCs in the In Vitro Studies |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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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 [31, 33]. Although conflicting results have been reported, such suppression of mixed lymphocyte reactions in vitro seem to arise from both contact-dependent [34] and soluble factors [33, 35]. 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 [27].
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 [31, 36]. Similarly, transforming growth factor-β1 is also involved in T-cell suppression by working with hepatocyte growth factor in promoting the allo-escaping phenotype [31]. In fact, Di Nicola and colleagues [31] showed that neutralizing antibodies to hepatocyte growth factor and transforming growth factor-β1 restored the proliferative response in mixed lymphocyte reactions [31]. Other suggested factors include interferon-
(INF-), tumor necrosis factor-
, and interleukin (IL)-2 [30, 33, 36]. 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 [27]. 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 [37, 38].
These immunosuppressive properties are retained even when co-stimulatory signals are added to the culture to upregulate the expression of MHC class II [35], or when T-cells are pre-cultured with INF- or re-challenged by the same MSCs [29–33, 39]. This indicates that MSCs can preserve their suppressive functions, even within sites of inflammation where inflammatory mediators could upregulate the expression of MHC antigens [28].
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 [3, 4]. Of course, this hypothesis is highly speculative at present. However, a recent clinical report demonstrating a better prognosis for patients with ischemic heart disease when their anti-inflammatory and pro-inflammatory cytokine ratio was higher in their blood seems consistent with such hypothesis [40].
Several studies have also shown that these immunosuppressive properties of the MSCs have no immunological restriction, and remain effective whether the stimulation is specific or nonspecific [31–33, 41], across species [32, 41, 42], and across different populations of lymphocytes [36, 42, 43]. In fact, Djouad and associates [42] showed that both human MSCs and murine MSCs could suppress xenogeneic mixed lymphocyte reactions in-vitro. Together, these results suggest that these immunosuppressive mechanisms may even cross species barriers.
Others have suggested different mechanisms depending on the stimuli. The tryptophan catabolizing enzyme indoleamine 2,3-dioxygenase has been suggested to play a role in the suppression of T-cell proliferation by MSCs [44]. When pre-treated by INF-, MSCs express indoleamine 2,3-dioxygenase activity that degrades essential tryptophan resulting in reduced lymphocyte proliferation. Nevertheless, indoleamine 2,3-dioxygenase-mediated tryptophan degradation is in disagreement with previous reports indicating that MSCs do not induce T-cells to undergo apoptosis [31, 33].
Marrow stem cells induced T-cell anergy has been proposed as another potential mechanism of immune suppression, partially attributed to the absence of co-stimulatory molecules on the MSCs [45]. Alternatively, MSCs can promote T-cell anergy by inducing their divisional arrest [46]. Glennie and colleagues [46] have shown that T cells stimulated in co-cultures with MSCs exhibited an extensive inhibition of cyclin-D2 and an upregulation of the cyclin-dependent kinase inhibitor p27kip1. However, the findings from different groups found that the unresponsiveness was only transient and relieved once MSCs were removed from the culture [31, 34]. The discrepancy between these studies may partially be due to different experimental conditions, the diverse stimuli used or the source of MSCs.
Furthermore, such immunosuppressive action had been shown to be partially mediated at another level through the generation of CD8+ regulatory cells (T-regs), which have potent suppressor activity [42, 43, 45, 47]. The mechanism of the induction of T-regs is still not well understood, involving different factors depending on the experimental conditions used [30].
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Interaction Between MSCs and Antigen-Presenting Cells |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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, INF-, and IL-12, and an increased production of the anti-inflammatory mediators such as IL-10 was also observed [43, 45]. In addition, the preferential activations of regulatory T cells were also shown to contribute to the delayed maturation of dendritic cells [49]. All these results suggest that MSCs can mediate allogeneic tolerance by directing antigen-presenting cells toward a suppressor phenotype that ultimately results in an attenuated T-cell response [28]. |
Interaction With NK Cells and Modulation of B-Cell Functions |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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production [35, 41, 50]. Transwell experiments have indicated that, although soluble factors are involved, cell-cell contact was also necessary to induce the observed inhibitory effect [51]. Finally, another level at which MSCs modulate immune responses is through the inhibition of B-cell proliferation, as well as their chemotactic behavior and antibody production [15, 52, 53]. Augello and colleagues [53] demonstrated the involvement of the programmed death-1 pathway in B-cell inhibition by MSCs [53]. Although the mechanisms are not yet fully understood, transwell experiments indicated that soluble factors are involved [52]. However, no in vivo evidence of the suppressive effect of MSCs on B cells is presently available.
Taken together, numerous studies provide strong evidence that MSCs are able to modulate the function of different immune cells in vitro through several interrelated mechanisms as summarized in Figure 1. In a recent review article, Aggarwal and Pittenger [45] reported that human MSCs constitutively secrete PGE2, hence altering the cytokine secretion profile of dendritic cells, naïve, and cytotoxic T-lymphocytes, as well as NK cells, namely by inhibiting tumor necrosis factor- and INF-, and by stimulating IL-10 secretion to modulate the immune cell response. By doing so, they inhibit the maturation and migration of various antigen-presenting cells, they suppress B-cell activation, and they induce suppressor T-cell formation [45]. Furthermore, through the release of IL-4, they accelerate a shift from a majority of pro-inflammatory Th1 cells toward an increase in the anti-inflammatory Th2 cells [27].
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Immunomodulation of MSCs In Vivo |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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Allogeneic MSCs transplants into ischemic myocardium of immunocompetent porcine recipients were reported by Caparrelli and colleagues [60] and Makkar and colleagues [61]. The implanted cells remained viable and differentiated without being rejected. In a swine and a rat model, Amado and colleagues [62] and Dai and associates [3], respectively reported the survival of allogeneic MSCs in infarcted myocardium without immunosuppression. Moreover, these cells were shown to differentiate and contribute to the functional improvement of the host myocardium. However, these findings were recently contradicted when Poncelet and colleagues [63] demonstrated that swine allogeneic MSCs did elicit a complete immune response accompanied with an increased concentration of allo-antibodies when injected into ischemic myocardium.
In November 2000, a fascinating study by Liechty and colleagues [64] was published in Nature Medicine. Well-characterized human MSCs were implanted into fetal sheep early in gestation. In this xenogeneic system, the human MSCs engrafted and persisted in multiple tissues for as long as 13 months after transplantation, even after maturation of the fetal immune system. Furthermore, these cells underwent site-specific differentiation into multiple cell lineages, including cardiomyocytes. Nevertheless, these experiments were carried out in fetal recipients.
In a series of studies at our laboratory, Saito and associates [65] injected intravenously labeled mice MSCs into immunocompetent adult rats, successfully producing stable cardiac chimeras for at least 12 weeks without any immunosuppression and with no evidence of rejection. It was confirmed that within days these mouse cells had homed into the bone marrow of the rats and after coronary artery ligation they were recruited to the peri-infarcted myocardium. In the following 4 to 6 weeks, the labeled cells were seen to differentiate into various phenotypes. In subsequent studies, MacDonald and colleagues [66] showed that not only stable chimeras were formed, but also the overall ventricular function was significantly improved. More recently, Atoui and associates [67] were able to confirm the engraftment of human MSCs within the rat myocardium for at least 8 weeks after myocardial infarction, and without the use of any immunosuppression. Such xenotransplant significantly contributed to the improvement in the overall cardiac function and in attenuating left ventricular remodeling.
However, tolerance of MSCs across the MHC barrier might not be absolute. Grinnemo and colleagues [68] demonstrated that although MSCs successfully engraft across allogeneic barriers, rejection occurs when a xenotransplant model is used in vivo. In this study, human MSCs could not be detected 1 week after implantation, and a massive infiltration was observed in the immunocompetent rats. Furthermore, peripheral lymphocytes of rats injected with human MSCs proliferated after re-stimulation with adult MSCs in vitro, suggesting cellular immunization. In their follow-up study, the same group demonstrated that the survival of human MSCs into ischemic rat myocardium is possible only when immunosuppression or immuno-incompetent hosts are used [69]. However, there seems to be some subtle differences in their experimental designs. For example, in their study, MSCs were harvested from the sternum of patients undergoing cardiac surgery. These cells were previously shown to have a lower capacity for differentiation, survival, and proliferation [13, 14]. It is of interest to note that in the in vitro studies, human MSCs used were harvested from young healthy donors [29, 45]. Still, further studies to clarify reasons for such contradictory findings will be highly desirable. Similar contradictory findings were also reported showing that despite retaining their immunosuppressive properties in vitro, allogeneic murine MSCs can be immunogenic in immunocompetent animals [70, 71]. Unexpectedly, these studies have also suggested that depending on the level of INF-, MSCs might also act as antigen-presenting cells [72]. The discrepancy observed could be explained by differences in the experimental conditions as a function of time, different stages of differentiation, or species diversity. For instance, several studies have described that the amount of fetal calf serum present in culture media can induce a significant immune response against cultured cells, even after an autologous transplantation [73]. In addition, it is clear that species-specific differences exist that may prevent engraftment of allogeneic or xenogeneic cells [30]. For example, MSCs derived from Balb-c mice do not express allo-antigens, whereas C57BL-6 mice are positive for MHC class I [34]. Transfer of C57BL-6-derived MSCs to Balb-c mice elicited an immune response, resulting in rejection [70]. By contrast, the immortalized C3 cell line survived in four different immunocompetent murine strains [42]. Finally, it should be mentioned that murine and human MSCs differ in the immunosuppressive potential. In fact, it was shown that the immunosuppressive effect of human MSCs, at least in vitro, is much stronger than that of murine MSCs [31, 36].
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The Immune Tolerance of MSCs After Differentiation |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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Comment |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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Although still not well defined, three broad mechanisms seem to contribute to this immuno-tolerance property. First, MSCs are hypo-immunogenic, expressing low levels or absence of MHC and co-stimulant molecules, as described earlier. Second, these stem cells inhibit T-cell responses directly by disrupting NK as well as CD8+ and CD4+ T-cell function, and indirectly through the modulation of B cells and antigen-presenting cells. Third, MSCs induce a local immunosuppressive environment through the production of prostaglandins and anti-inflammatory cytokines. It is possible that some of the beneficial effects of MSCs might reflect, in part, the protective and immunosuppressive activities they exert on injured tissues [30]. It is of interest to note that some mechanisms previously described have recently been implicated in the survival of the fetal allograft [77].
Based on these clinical and experimental data that have been previously discussed, the Food and Drug Administration recently approved an phase I, multicenter clinical trial sponsored by Osiris Inc (Baltimore, MD) in which allogeneic human MSCs were given intravenously without immunosuppression to patients after an acute myocardial infarction. The preliminary results recently presented were highly encouraging [78].
The potential importance of these findings for the treatment of ischemic heart disease is apparent. Due to their immunotolerance property, the establishment of MSCs as effective "universal donor cells" [67] could dramatically expand the therapeutic potential for cellular cardiomyoplasty. From a clinical perspective, these cells could be isolated and expanded from donors irrespective of their MHC haplotype, tested for their functional capabilities well in advance, and stored as an "off-the-shelf" cell population for immediate use when needed on any patient after an acute myocardial infarction. Such medical and logistic advantages are not available with the use of autologous MSCs, which is currently the cell source of choice. Perhaps more importantly, because such allogeneic MSCs can be obtained from young healthy donors, they could be of great value in patients with genetic cardiomyopathies and in elderly patients with multiple medical comorbidities whose own MSCs could be dysfunctional.
Despite the exciting preliminary results, however, further investigations are required to address many of the remaining controversial findings and better assess the efficacy and safety of allogeneic MSCs, as well as the important question of chronic rejection after cell transplantation. Furthermore, further mechanistic studies related to the observed improvement in ventricular function and more quantitative assessment of MSCs engraftment are still needed before the therapeutic promise of these cells can be fully achieved [15].
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Acknowledgments |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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References |
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TopAbstractIntroductionThe Proliferating Sources of...MSCs and Their Immunotolerant...Immunomodulatory Role of MSCs...Interaction Between MSCs and...Interaction With NK Cells...Immunomodulation of MSCs In...The Immune Tolerance of...CommentAcknowledgmentsReferences |
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does not break, but promotes the immunosuppressive capacity of adult mesenchymal stem cells Clinic Exp Immunol 2007;149:353-363.-stimuated marrow stromal cells; a new type of nonhematopoietic antigen-presenting cell Blood 2006;107:2570-2577.This article has been cited by other articles:
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  A. Shafy, T. Lavergne, C. Latremouille, M. Cortes-Morichetti, A. Carpentier, and J. C. Chachques Association of electrostimulation with cell transplantation in ischemic heart disease J. Thorac. Cardiovasc. Surg., October 1, 2009; 138(4): 994 - 1001. [Abstract] [Full Text] [PDF]
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 A. M. Abarbanell, A. C. Coffey, J. W. Fehrenbacher, D. J. Beckman, J. L. Herrmann, B. Weil, and D. R. Meldrum Proinflammatory cytokine effects on mesenchymal stem cell therapy for the ischemic heart. Ann. Thorac. Surg., September 1, 2009; 88(3): 1036 - 1043. [Abstract] [Full Text] [PDF]
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 G. Valen Extracardiac approaches to protecting the heart Eur. J. Cardiothorac. Surg., April 1, 2009; 35(4): 651 - 657. [Abstract] [Full Text] [PDF]
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Q. Zhao, Y. Sun, L. Xia, A. Chen, and Z. Wang Randomized Study of Mononuclear Bone Marrow Cell Transplantation in Patients With Coronary Surgery Ann. Thorac. Surg., December 1, 2008; 86(6): 1833 - 1840. [Abstract] [Full Text] [PDF]
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R. C.J. Chiu Invited Commentary Ann. Thorac. Surg., December 1, 2008; 86(6): 1848 - 1848. [Full Text] [PDF]
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