Allogeneic Mesenchymal Stromal Cells Transplanted Onto the Heart Surface Achieve Therapeutic Myocardial Repair Despite Immunologic Responses in Rats

Abstract

Background Transplantation of allogeneic mesenchymal stromal cells ( MSC s) is a promising treatment for heart failure. We have shown that epicardial placement of cell sheets markedly increases donor cell survival and augments therapeutic effects compared with the current methods. Although immune rejection of intramyocardially injected allogeneic MSC s have been suggested, allogeneic MSC s transplanted on the heart surface (virtual space) may undergo different courses. This study aimed to elucidate immunologic response against epicardially placed allogeneic MSC s, rejection or acceptance of these cells, and their therapeutic effects for heart failure. Methods and Results At 4 weeks after coronary artery ligation, Lewis rats underwent epicardial placement of MSC sheets from syngeneic Lewis or allogeneic Fischer 344 rats or sham treatment. At days 3 and 10 after treatment, similar ratios (≈50% and 30%, respectively) of grafted MSC s survived on the heart surface in both MSC sheet groups. By day 28, survival of syngeneic MSC s was substantially reduced (8.9%); survival of allogeneic MSC s was more extensively reduced (0.2%), suggesting allorejection. Correspondingly, allogeneic MSC s were found to have evoked an immunologic response, albeit low level, as characterized by accumulation of CD 4 + T cells and upregulation of interleukin 6. Despite this alloimmune response, the allogeneic MSC sheet achieved myocardial upregulation of reparative factors, enhanced repair of the failing myocardium, and improved cardiac function to the equivalent degree observed for the syngeneic MSC sheet. Conclusions Allogeneic MSC s placed on the heart surface evoked an immunologic response; however, this allowed sufficient early phase donor cell survival to induce equivalent therapeutic benefits to syngeneic MSC s. Further development of this approach toward clinical application is warranted.