Abstract 1842: Progenitor Cells from the Recipient Generate Immunocompatible Myocardium within the Transplanted Dog Heart
Chronic rejection, accelerated cardiac allograft vasculopathy, myocardial infarction and ischemic heart failure determine the unfavorable evolution of the transplanted heart in humans. Here we tested whether cardiac pathology in the dog model of cardiac transplantation can be corrected partly by a strategy that implements the use of cardiac progenitor cells (CPCs) from the recipient to repopulate the donor heart with immunocompatible cardiomyocytes and coronary vessels. Importantly, canine CPCs have been characterized in vitro and in vivo. A female donor heart was transplanted in a male recipient and CPCs from the explanted heart were infected with a lentivirus carrying EGFP, so that the presence of the Y-chromosome and the expression of EGFP were employed as markers of the progeny of the injected cells in the donor heart. Intracoronary delivery of CPCs occurred ~3 weeks after surgery and 3 additional administrations of CPCs were done at weekly intervals and dogs were sacrificed ~3– 4 weeks after the last injection. To evaluate quantitatively the effects of recipient CPCs on the cardiac allograft, 125–130 samples were processed in each heart. Clusters of newly formed EGFP-positive myocytes and coronary vessels were detected in almost all specimens of both ventricles. Myocyte and coronary vessel regeneration was demonstrated by immunocytochemistry and confocal microscopy and was confirmed by detection of EGFP DNA and the Sry gene located in the Y-chromosome. Additionally, the detection of the Y-chromosome by FISH confirmed the male genotype of EGFP-myocytes and vascular structures. A significant number of myocytes reached the adult phenotype together with large, intermediate and small coronary arteries and capillary profiles. The regenerated myocytes expressed connexin 43 and N-cadherin and were essentially indistinguishable from resident donor myocytes. Our data suggest that a large number of cardiomyocytes and coronary vessels are created in a short period from differentiation of CPCs from the recipient. Ultimately, the recipient-derived myocardium may govern the behavior of the transplanted heart, and immunosuppressive therapy may no longer be required improving quality of life and lifespan of patients with cardiac transplantation.