Cell transplantation with human mesenchymal or embryonic stem cells to the heart : Experimental, molecular, immunological and echocardiographic studies

Abstract: Background: Human mesenchymal stem cells (hMSC), human embryonic stem cells (HESC) and human fetal cardiomyocyte progenitor cells (HFCP) all represent possible candidate cells for regeneration of damaged myocardium. Although they represent cell types with many positive attributes, their capacity to engraft, to differentiate into mature cardiomyocytes, to improve myocardial function and their immunological properties are the focus of these studies. Methods and Results: hMSC were rejected from the myocardium of immunocompetent rats even if immunosuppression with Tacrolimus was used. Re-exposure of hMSC to lymphocytes from rats previously exposed to hMSC caused a significant proliferation indicating a sensitization reaction. The hMSC survived in the myocardium of athymic T-cell deficient rats and in an ischemic rat model the survival of the hMSC increased when Tacrolimus was added. Even though the hMSC survived in the ischemic myocardium they did not differentiate into cardiomyocytes or improve the myocardial function. HESC have the ability to differentiate into cardiomyocytes, but a major obstacle to clinical application is their immunological characteristics. We have shown that HESC express HLA class I, no HLA class II and low levels of costimulatory molecules. HESC are immunologically inert and do not inhibit immune responses during direct or indirect antigen presentation and HESC were acutely rejected when transplanted over the xenogeneic barrier into mice. In order to study the possibility to induce tolerance towards in vivo differentiating HESC, these were implanted into the testis and heart of immunocompetent mice treated with costimulation blockade. The HESC developed into teratoma in the testis in all mice and induced regulatory T-cells to undifferentiated HESC when transplanted into the heart. When costimulation blockade was repeated HESC engrafted in the myocardium in one of five mice. Islet-1 positive cells were identified in the atria and outflow tracts of aborted human fetal hearts. We succeeded to isolate and culture the Islet-1 positive cells and their progeny in a reproducible manner, forming spontaneously beating cardiospheres and monolayers. Implantation of the HFCP formed stable engraftments in the myocardium of SCID mice. Conclusions: hMSC are immunogenic in xenogeneic settings and they do not improve myocardial function or differentiate into cardiomyocytes in a rat ischemia model. HESC are also immunogenic in allogeneic and xenogeneic settings. Costimulation blockade is sufficiently robust to induce tolerance to HESC in an immune-privileged environment like testis. HESC transplanted into the myocardium of immunocompetent mice induced regulatory T-cells and when the costimulation blockade was repeated the success of transplantation was similar to that seen in SCID mice. The cardiomyocyte origin of the HFCP, their capacity to grow in culture and their formation of stable engraftments in the myocardium make the HFCP a putative candidate for cardiomyoplasty.