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Right arrow Transplantation - heart

Ann Thorac Surg 2004;77:737-744
© 2004 The Society of Thoracic Surgeons

Review

Immunosuppression and xenotransplantation of cells for cardiac repair

Yong-Fu Xiao, MD, PhDa*, Jiang-Yong Min, MDa, James P. Morgan, MD, PhDa

a Stem Cell Research Laboratory, The Charles A. Dana Research Institute and The Harvard-Thorndike Laboratory, Cardiovascular Division, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA

* Address reprint requests to Dr Xiao, Cardiovascular Division, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Ave, Boston, MA 02215, USA
e-mail: yxiao{at}bidmc.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Cellular xenotransplantation for...
 Immunoreaction of cellular...
 Comment
 Acknowledgments
 References
 
The death of highly vulnerable cardiomyocytes during ischemia leads to cardiac dysfunction, including heart failure. Due to limited proliferation of adult mammalian cardiomyocytes, the dead myocardium is replaced by noncontractile fibrotic tissue. Introducing exogenous cells to participate in the regeneration of infarcted myocardium has thus been proposed as a novel therapeutic approach. In view of the availability of various xenogeneic cells and fewer ethical and political concerns that surround human embryonic stem cells and fetal cardiomyocytes, cellular xenotransplantation may be a potential alternative approach for cardiac repair in humans. However, one of the most daunting challenges of xenotransplantation is immunorejection. This article summarizes the progress in cellular xenotransplantation for cardiac repair in experimental settings and the current understanding of possible immune responses following the engraftment of xenogeneic cells. The public attitude towards xenotransplantation is reportedly more favorable to receiving cells or tissues than a whole organ, but many scientific obstacles need to be overcome before the utilization of xenogeneic cells for cardiac repair in patients with heart disease becomes applicable to clinical practice.


   Introduction
Top
 Abstract
 Introduction
Cellular xenotransplantation for...
 Immunoreaction of cellular...
 Comment
 Acknowledgments
 References
 
Myocardial infarction (MI) is one of the leading causes of progressive heart failure that has a high mortality in cardiac patients. Clinically, several therapies are available for physicians to improve the prognosis of heart failure. At the present time, heart transplantation is probably the most effective therapy for a patient with end-stage heart failure. However, extremely high expenses, complexity of immunoreaction, and significant shortage of donor hearts limit this therapy for the most patients who desperately need heart transplantation. Therefore, cellular approaches for the treatment of heart failure have emerged. Transplantation of exogenous cells into injured myocardium, a procedure known as cellular cardiomyoplasty (CCM), has been established and improved cardiac function in both animal models [1–4] and patients [5–8] and is currently undergoing evaluation.

Studies have demonstrated the feasibility of transplantation of xenogeneic, allogeneic, and autologous cells into normal or injured myocardium in different species [9–16]. Transplantation of cardiomyocytes [17], bone marrow cells [3], human mesenchymal stem cells (hMSCs) [18], or mouse embryonic stem cells (ESCs) [4, 19, 20] improved cardiac function in MI [3, 4, 17–20] and myocarditic animals [21]. Intracoronary [5, 6] or transendocardial [8] transplantation of autologous mononuclear bone marrow cells improved heart function in patients with MI [5, 6] or end-stage ischemic heart disease [8].

Autologous or allogeneic transplantation of adult stem cells are available for cellular cardiomyoplasty, but their plasticity has been challenged in vivo and in vitro [22–24]. As pluripotent ESCs are able to differentiate into cardiomyocytes, whereas the clinical use of human ESCs raises serious ethical and political concerns, an alternative strategy is to transplant xenogeneic ESCs for cardiac repair. Recent results show that cotransplantation of human fetal cardiomyocytes (hFCs) can produce a significantly greater improvement of cardiac function in MI pigs than transplantation hMSCs alone [18]. Ethical, political, and religious issues, however, will strongly challenge the clinical use of hFCs. Therefore, xenogeneic fetal cardiomyocytes could be considered as a cell source for transplantation or cotransplantation in diseased human hearts. This article summarizes the experimental developments of immunosuppression and cellular xenotransplantation for cardiac repair. The research progress of CCM with autologous or allogeneic cells has been presented in several other reviews [25–30].


   Cellular xenotransplantation for cardiac repair
Top
 Abstract
 Introduction
 Cellular xenotransplantation for...
Immunoreaction of cellular...
 Comment
 Acknowledgments
 References
 
Somatic cells
The xenotransplantation of cardiac muscle cells for repairing damaged myocardium has been studied for many years. A successful transplantation of mouse cardiomyocytes into the hearts of immunosuppressed rats was reported a decade ago [31, 32]. In adult swine with immunosuppressive treatment (15 mg/kg cyclosporine, b.i.d.), Van Meter and his colleagues transplanted mouse atrial cardiomyocyte tumor cells (AT-1, xenogeneic), neonatal porcine myocytes (allogeneic), and human fetal cardiomyocytes (xenogeneic) into the left ventricular wall [33]. The surviving engrafts contained cardiac cell architecture and formed close associations with host myocytes [33]. Lately, Leor and colleagues [34] transplanted tissue fragments of human fetal ventricles into myocardial scar in cyclosporine-treated rats. Histologic analysis revealed the presence of grafted human cardiomyocytes in the infarcted area up to 14 to 65 days after transplantation (Table 1). In addition, HL-1 cells (a cardiac muscle cell line derived from AT-1 cells) were grafted into the normal myocardium and the middle of the infarcted area in pigs treated with immunosuppressive compounds [35]. Four to 5 weeks after the cell transplantation, implanted HL-1 cells induced a marked increase in angiogenesis and formed stable grafts and gap junctions among the grafted and host myocardial cells in normal myocardium, but not in infarct tissues [35]. More recently, rat fetal cardiomyocytes, with blocking the CD28/B7 costimulatory pathway via CTLA-4-Ig gene transfer, were successfully xenotransplanted into the normal myocardium of mice [36].


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  		Table 1. Cellular Xenotransplantation for Cardiac Repair

 
These results suggest that xenografted cardiomyocytes could survive in host myocardium and form connection with host myocytes, but immunosuppressive therapy or genetic manipulation of donor cells to reduce immunorejection was required (Table 1). Meanwhile, the improvement of injured heart function has not been reported in the studies with transplantation of xenogeneic cardiomyocytes.

Adult stem cells
Several studies have shown that adult stem cells have the capacity to generate cardiomyocytes in vitro [26, 37] and in vivo [3, 18, 38]. The transplantation of adult stem cells derived from bone marrow, including stromal and mesenchymal cells, or from skeletal muscle, such as satellite cells, improves the damaged heart function in animals [3, 18] and in humans [5–8].

Bone marrow stem cells
Recently, Saito and colleagues [39] studied the fate of mouse marrow stromal cells xenotransplanted into fully immunocompetent adult rats without any immunosuppressive treatment. One week after the systemic transplantation of mice stromal cells, the rats underwent coronary artery ligation and were sacrificed for histologic and immunohistochemical analysis. Labeled mouse cells were engrafted into the bone marrow cavities of the recipient rats for at least 13 weeks after the transplantation. Numerous mouse cells were also found in the infarcted myocardium and stained positively against cardiomyocyte specific proteins (Table 1, [39]).

Our previous study showed that transplantation of hMSCs or cotransplantation of hMSCs with hFCs (1:1) significantly improved cardiac function in MI pigs, but the improvement was significantly greater in the MI animals that received cotransplantation [18]. Histology demonstrated cardiac differentiation of xenografts. Immune tolerance was achieved for 6 weeks via a modest dose of cyclosporine, 15 mg/kg every other day (Table 1, [18]). Additionally, hMSCs were tested to undergo myogenic differentiation after they were xenotransplanted into adult murine myocardium [38]. Human mesenchymal stem cells labeled with lacZ were injected into the left ventricle of immunodeficient adult mice. None of the engrafted hMSCs expressed myogenic markers 4 days after injection, but after 7 days or more, some surviving cells morphologically resembled at the surrounding host cardiomyocytes and expressed desmin, ß-myosin heavy chain, {alpha}-actinin, cardiac troponin T, and phospholamban at levels comparable to those of the host cardiomyocytes. The sarcomeric organization of the contractile proteins was also observed in the grafts. These results indicate that hMSCs xenografted into mouse myocardium appeared to differentiate into cardiomyocytes (Table 1, [38]).

Satellite cells
Unlike adult mammalian cardiomyocytes, skeletal muscle has the ability to self-repair after injury because of its precursor cells, satellite cells, or myoblasts. Reinecke and colleagues showed [40] that xenotransplantation of primary mouse C2C12 myoblasts into rat myocardium caused transmural replacement of the left ventricular wall and distorted the epi- and endocardial contours. The C2C12 grafts showed substantially higher 5-bromo-2'-deoxyuridine incorporation rates. It is concluded from the study that when sufficient amounts of proliferation occur after grafting, skeletal muscle cells can effectively replace the volume of lost myocardium. Recently, Haider and colleagues [41] have reported that engrafted human skeletal myoblasts in injured porcine myocardium survived for a long term by transient application of a minimal dose of cyclosporine (5 mg/kg/d). The immunosuppression started 5 days before cell transplantation and continued only for 6 weeks after transplantation, but the xenoengrafted human myoblasts were observed in porcine myocardium with chronic ischemia and infarction up to 7 months without signs of immunorejection (Table 1 [41]).

The success of xenotransplantation of adult stem cells suggests that adult stem cells are probably able to adapt to a xenogeneic environment. Immunosuppressive therapy may be minor or not required after stem cell xenotransplantation. Xenografted adult stem cells also hold the promise of the improvement of injured heart function (Table 1).

Embryonic stem cells
Embryonic stem cells have the capacity to spontaneously differentiate into cardiomyocytes if a proper environment is provided. Cardiomyocytes derived from cultured mouse ESCs have electrophysiological characteristics similar to those in adult cardiomyocytes [42–44] and exhibit cell morphology, sarcomere formation, and cell-cell junctions similar to those observed in cardiomyocytes in vivo [45–48]. Human ESCs are also able to spontaneously differentiate into cardiomyocytes if conditions in vitro are allowed [49, 50]. The cardiac-like cells derived from human ESCs show positive and negative chronotropic responses to the stimuli of isoproterenol and carbamylcholine, respectively [49]. In addition, cardiac differentiation could be enhanced by treatment of human ESCs with 5-aza-2'-deoxycytidine [50].

Several studies have investigated the effects of xenotransplantation of mouse ESCs on cardiac function in infarcted animal models. Min and colleagues locally transplanted ESCs tagged with green fluorescent protein (GFP) into injured myocardium in a rat MI model [4]. Compared to the control MI animals, cardiac function was significantly improved in ESC-grafted MI rats 6 weeks after cell transplantation. Double immunostaining against GFP and cardiac sarcomeric {alpha}-actin, {alpha}-myosin heavy chain, or troponin I showed the cardiac differentiation of xenografts in MI hearts. Additionally, isolated single cells showed rod-shaped GFP positive myocytes with clear striations in ESC-transplanted animals. The shape and size of GFP positive myocytes did not significantly differ from those of host cardiomyocytes [4]. The long-term survival of mouse ESCs xenotransplanted into injured myocardium was also observed in MI rats without the treatment of immunosuppression [19]. During the observation period of 32 weeks after ESC implantation, the survival rate was significantly increased in MI rats. Hemodynamic and echocardiographic data showed significant improvement of cardiac function in the cell-transplanted MI group (Table 1). Green fluorescent protein-positive tissue was identified in the injured myocardium and stained positively by the antibodies against several specific cardiac proteins [19].

A similar finding was also reported by another group in rats with ligation of the left coronary artery [51]. Cells dissected from beating regions of embryoid bodies (EBs) formed by GFP-tagged mouse ESCs were injected into the border zone between the infarcted myocardium and normal myocardium. Thirty days after transplantation, GFP-expressed cells were detected and stained positively by the antibody against sarcomeric myosin [51]. In addition, mouse ESCs were injected into the area surrounding the infarcted tissue in MI rats without immunosuppressive therapy [52]. Engrafted fluorescent cells displayed a typical cardiac phenotype, including sarcomeric striations, and immunostaining positively for the ventricle-specific myosin light chain (MLC2v) and gap junction protein connexin-43. Echocardiography showed significant improvement of left ventricular ejection fraction in the cell-transplanted rats [52].

The experimental data show that xenotransplanted mouse ESCs in a rat host myocardium express the typical characteristics of heart cells and improve damaged heart function. The intriguing point of these studies is that the recipients of xenotransplantation of mouse ESCs did not receive any immunosuppressive treatment (Table 1).


   Immunoreaction of cellular xenotransplantation for cardiac repair
Top
 Abstract
 Introduction
 Cellular xenotransplantation for...
 Immunoreaction of cellular...
Comment
 Acknowledgments
 References
 
Bone marrow stem cells
The successful xenotransplantation of adult stem cells without immunosuppression [39] raises an interesting topic; namely, whether bone marrow stem cells share the privilege of immune tolerance as ESCs [53]. Table 2 summarizes our recent results of xenotransplantation of hMSCs alone or plus hFCs in MI pigs with or without immunosuppressive therapy. The improvement of cardiac function in postinfarcted pigs that have received cotransplantation of hMSCs and hFCs without immunosuppression was similar to the MI animals that have received hMSCs alone with immunosuppression. We speculate that the improvement of cardiac function probably results from the engrafted hMSCs, not from hFCs, because FCs are differentiated somatic cells and may not share the immune privilege of stem cells. The immune privilege of hMSCs is evidenced by a long-term survival (13 months) of hMSCs, even after their differentiation into many cell types including cardiomyocytes, in an immunocompetent sheep after utero transplantation [54]. The precise mechanism for the survival of xenografted mice stromal cells in immunocompetent rats and hMSCs in immunocompetent MI porcine hearts or in immunocompetent sheep uteri remains unclear. Saito and colleagues [39] cited the "danger model" hypothesis [55–57] as part of the explanation for their interesting results. However, it is not clear whether the difference in species between donor cells and recipients plays a role in the immune tolerance of xenotransplantation of adult stem cells. Recently, hMSCs were successfully xenografted in murine animals [38], but the mice were genetically immunodeficient. It will be interesting to know whether hMSCs can survive in immunocompetent rodents or whether mice stromal cells will survive in other immunocompetent species.


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  		Table 2. Left Ventricular Function in Postinfarcted Pigs at 6 Weeks After Cell Transplantation

 
Compared to adult stem cells, the success of xenotransplanted somatic cells requires genetic manipulation of donor cells or immunosuppressive therapy in recipients (Table 1, somatic cells). It has been found that neonatal pig cardiomyocytes were rejects after local transplantation even with reinforced immunosuppressive compounds, whereas transplanted HL-1 or fetal pig cardiomyocytes survived and formed gap junctions with the host cardiomyocytes [35]. The survival of xenotransplanted HL-1 or fetal cardiomyocytes is probably due to their less immunogenic effect compared to relatively matured neonatal cardiomyocytes. In the other study, however, fetal rat cardiomyocytes, transplanted into left ventricular scar tissue of the adult rat heart, are eventually rejected despite prolonged immunosuppression [58].

Embryonic stem cells
The rejection of the xenografted mouse ESCs was not noted in the host rats without immunosuppressive therapy (Table 1, [4, 19, 51, 52]). The xenograft acceptance presumably resulted from the nature of the cells with less expression of the major histocompatibility complex (MHC) antigen [59] and(or) the relatively privileged transplantation site, myocardium, where presentation and recognition of MHC antigen may not take place because of the lack of a lymphatic drainage system [60]. However, the underlying mechanisms remain to be delineated for the immune tolerance of xenografted mouse ESCs into immunocompetent rat hearts. It has been known that ESCs do not express many membrane surface antigens [61] and share immune-privileged features relevant for tolerance induction [53]. Embryonic tissue also possesses a range of proteins, which efficiently counteract maternal T cells responses [53]. Therefore, the tolerance of cellular xenografts in immunocompetent animals probably correlates with the degree of differentiation of the donor cells. Embryonic stem cells are the most plastic cells and presumably more easily adaptable to a new environment, even in a xeno-host.

So far, there is no clear answer to the question why the recipients do not reject the xenografted ESCs after their differentiation, even if the stem cells are immune-privileged. One possible explanation is that the establishment of chimerism may occur at the early stage after cell transplantation. Cross talks may happen between engrafted cells and host cells, which modulates the expression of antigens of donor cells and also the immune response of a host. It has been demonstrated that after cell transplantation, stem cells can down-regulate the host immune response and induce mixed immune chimerism favoring long-term graft acceptance [59, 62, 63]. Engrafted stem cells can also suppress the function of mature T cells, either directly or by stimulating suppressor T cells, and thus are tolerogenic [64]. In addition, ESCs probably contain a smaller pool of T cells, which is critical in the induction of transplant tolerance [65, 66]. Experiments show that suppression of T cells results in long-term survival of mouse hearts xenografts in C6-deficient rats [67]. Another explanation for xenotransplant tolerance is that engrafted ESCs in myocardium undergo cardiac differentiation. During the differential process, the expression of surface antigens of grafted cells is influenced or determined by the local microenvironment of a host heart. Indeed, it has been observed that differentiating stem cell-derived cardiomyocytes undergo structural adaptation and mobilize the nuclear transport regulator in support of nucleocytoplasmic communication during commitment to mature cardiac lineage [68]. Additionally, the natural selection of implanted cells may occur after ESC transplantation, which may mean that the survived cells in a recipient heart are less immunogenic or "dangerous." More careful experiments are required to confirm these possibilities or speculations.

Rationale and challenge for the researches on cellular xenotransplantation
Compared to donor hearts, autologous or allogeneic bone marrow stem cells are more available for cellular cardiomyoplasty. Clinical trials show that the autologous transplantation of bone marrow cells promotes neovascularization and produces a functional benefit [5–8]. However, the plasticity of adult stem cells to transdifferentiate to cardiomyocytes has been challenged [70]. In vitro, rat bone marrow stromal cells failed to transdifferentiate into cardiomyogenic phenotype cells [22]. Reinecke and colleagues showed that skeletal muscle stem cells did not transdifferentiate into cardiomyocytes after cardiac grafting [23]. The transplantation of bone marrow hematopoietic stem cells robustly reconstituted peripheral blood leukocytes in lethally irradiated mice, but did not contribute appreciably to nonhematopoietic tissues, including brain, kidney, gut, liver, and muscle [24]. Therefore, the transdifferentiation of circulating hematopoietic stem cells and(or) their progeny is probably an extremely rare event. Spontaneous cell fusion has been postulated as a possible mechanism of transdifferentiation of bone marrow cells [70] or neuronal progenitor cells [71] into unexpected cell lineages. Our previous results showed that transplantation of hMSCs alone produced much less improvement of cardiac function than cotransplantation of hMSCs with hFCs in MI pigs with immunosuppressive therapy [18]. The transplantation of ESCs alone, however, significantly enhanced heart function in MI animals [4, 19, 52]. Since the clinical use of human fetal cardiomyocytes and human ESCs raises serious ethical and political concerns, xenotransplantation of the specific cell types may be a potentially alternative strategy.

Immunorejection of xenografted cells challenges the practical application of cell therapy. Genetic alteration of donor cells can increase their surviving chance in a xenogeneic recipient. A logical target for genetic manipulation of donor cells is the genes encoded by MHC [72] or immunoglobulins [73]. Setting aside ethical and technical problems, nuclear transfer techniques may also be able to derive genetically less immunogenic cells for individual patients. A recent study in mice demonstrated a particularly elegant combination of nuclear transfer, stem cell isolation, and tissue transplantation [74]. Genetic modulation, therefore, may overcome species barrier and create immunotolerant cells for clinical xenotransplantation in the future.

Except for the similar challenges for autologous or allogeneic cell transplantation discussed in the other reviews [25–30, 69, 75, 76], the risk of transmission of animal pathogens is an additional factor limiting the use of xenogeneic cells for cardiac repair in human beings. For example, transgenic pig cells are favored as a potential source for xenotransplantation, but they may carry pathogens, some of which are able to infect human cells [77]. The porcine endogenous retroviruses (PERVs) are integrated in the pig genome as proviruses. Experimental results demonstrated that PERVs in vitro infected numerous different types of human primary cells and cell lines [78]. In contrast, inoculation of guinea pigs, rats, and minks with PERVs did not induce productive infection [78, 79]. Furthermore, inoculation of monkeys and baboons with high titers of a human-adapted PERV to simulate a situation of xenotransplantation did not produce antibodies against PERV or integration of proviral DNA in blood cells or cells of several organs. The apparent difference in the outcomes in vitro and in vivo might result from an efficient elimination of the virus by the innate or adaptive immunity of the animals [80]. In contrast, a recent study showed that porcine cytomegalovirus was transmitted to the recipients in pig-to-primate xenotransplantation [80]. Vaccinating or specified pathogen-free breeding may be possible to eliminate all of the known porcine microorganisms in the future, but more careful experiments are surely required to ensure the xenogeneic cell to be pathogenic free before it is used for cell therapy in patients.


   Comment
Top
 Abstract
 Introduction
 Cellular xenotransplantation for...
 Immunoreaction of cellular...
 Comment
Acknowledgments
 References
 
A recent survey shows that public perceptions of xenotransplantation are more positive in receiving cells and tissue than in receiving a whole organ. An overwhelming 80% of the public and about 90% of the patients in the survey were in favor of continued research on xenotransplantation [81]. This review summarizes the successful xenotransplantation of cells for cardiac repair in animal models. Engrafts of xenogeneic cells in injured myocardium have demonstrated restoration of myocardial structure and improvement of cardiac function. The advantages of using ESCs for cellular cardiomyoplasty are the great plasticity, proliferative capacity, and possibly immune-privileged features. Genetic manipulation can further enhance cellular xenograft tolerance [73, 82]. However, whether the host rejects xenogeneic stem cells has not been examined in human trials. Clinical utility of xenogeneic cells for the therapy of heart disease still has a long way to go, but scientific significances of cellular xenotransplantation can never be overemphasized.


   Acknowledgments
Top
 Abstract
 Introduction
 Cellular xenotransplantation for...
 Immunoreaction of cellular...
 Comment
 Acknowledgments
References
 
We are grateful to our colleagues for their contributions in our stem cell research project.


   References
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 Abstract
 Introduction
 Cellular xenotransplantation for...
 Immunoreaction of cellular...
 Comment
 Acknowledgments
 References
 

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