Stem cell engraftment in a heterotopic cardiac hamster-to-rat xenotransplantation model

Introduction: The hamster-to-rat species combination is considered a concordant difficult xenotransplantation model that resembles the immunological situation observed when transplanting hDAF pig organs into non-human primates. The aim of the present study was to investigate in a hamster-to-rat cardiac model the capacity of progenitor stem cells to engraft the transplanted heart and transdifferentiate into cardiomyocytes. Material and methods: A heterotopic cardiac transplantation procedure was performed between Golden Syrian hamsters (Harlan Italia) which served as organ donors and green fluorescent protein (GFP) transgenic Sprague– Dawley rat (Japan SLC) recipients. Recipients underwent splenectomy during the transplantation procedure and were treated by intramuscular cyclosporine A (Novartis) at a dose of 15 mg/kg/day throughout the postoperative period. As a control, a group of GFP transgenic recipients underwent allogeneic heterotopic heart transplantation and immunosuppression by the administration of cyclosporine A. The transplanted hearts were harvested on postoperative day 15 and analyzed histologically for the presence of GFP positive cells. The GFP positive cells were characterized for specific muscle differentiation markers and analyzed by immunofluoresence and confocal microscopy. Results: A high number of GFP positive cells were found in the xenotransplanted hamster hearts, however the majority were inflammatory in nature. In four out of six (67%) cases analyzed, a limited number of GFP positive cardiac cells with shape and morphology compatible with that of mature cardiomyocytes were found. It is noteworthy that these cells expressed cardiomyocyte-specific markers such as desmin and myosin heavy chain. In the allotransplanted group similar GFP positive cardiac cells were observed in 10 out of 12 (83%) cases. Conclusions: The heterotopic cardiac hamster-to-rat xenotransplantation model is an appropriate animal model to study stem cell engraftment in damaged hearts after a transplant procedure between different species. Our preliminary data also suggest that also a xenogeneic environment may provide adequate mediators and cell signals to allow donor stem cell engraftment and differentiation into cardiomyocytes. Fusion vs. transdifferentiation events are currently under examination.