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

Abstract

BackgroundTransplantation of allogeneic mesenchymal stromal cells (MSCs) 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 MSCs have been suggested, allogeneic MSCs transplanted on the heart surface (virtual space) may undergo different courses. This study aimed to elucidate immunologic response against epicardially placed allogeneic MSCs, rejection or acceptance of these cells, and their therapeutic effects for heart failure.Methods and ResultsAt 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 MSCs survived on the heart surface in both MSC sheet groups. By day 28, survival of syngeneic MSCs was substantially reduced (8.9%); survival of allogeneic MSCs was more extensively reduced (0.2%), suggesting allorejection. Correspondingly, allogeneic MSCs were found to have evoked an immunologic response, albeit low level, as characterized by accumulation of CD4+ 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.ConclusionsAllogeneic MSCs 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 MSCs. Further development of this approach toward clinical application is warranted.

Comparative proteomic analysis of extracellular vesicles isolated from porcine adipose tissue-derived mesenchymal stem/stromal cells

“…One particularly attractive application is in cardiovascular disease, the leading cause of mortality in countries with developed and emerging economies3. Indeed, a progressively increasing number of studies has focused on the ability of MSCs to repair the damaged myocardium in murine models of hypertension and heart failure45. Furthermore, in recent years, we and others have tested the efficacy of MSCs for attenuating cardiac and renal injury in large animal models of cardiovascular disease6.…”

Application of tissue‐engineered pericardial patch in rat models of myocardial infarction

“…In a study by Tano et al myocardial function, cell survival and tissue regeneration were compared following cell therapy through intra‐myocardial injection and epicardial cell‐sheet implantation (scaffold free). This demonstrated enhanced cardiac function and tissue structure as well as higher cell survival in the epicardial implantation approach as compared with intra‐myocardial injection of MSCs …”

“…This demonstrated enhanced cardiac function and tissue structure as well as higher cell survival in the epicardial implantation approach as compared with intra-myocardial injection of MSCs. 15 To ameliorate stem cell engraftment, several approaches have been investigated including genetic manipulation of cells to increase homing and survival as well as tissue engineering techniques involving preparation of scaffolds. 5,[16][17][18][19] Scaffolds that are derived from decellularized natural tissues appear to be appropriate and efficient as they possess the essential natural tunnels for vessels and nerves as well as the porosity to nest-specific cell lineage.…”

Stem cell-derived cell sheet transplantation for heart tissue repair in myocardial infarction

“…We must be aware that the safety of such cell sheet should be carefully checked before clinical application. Tano and his colleagues reported that allogeneic rat mesenchymal stromal cells improved cardiac function to an equivalent degree compared to syngeneic MSC sheet despite an immunologic response without immunosuppressive drugs [96].…”