Allogeneic stem cell therapy for cardiac repair and host immune response

Abstract

Bone marrow derived allogeneic (unrelated donor) mesenchymal stem cells (MSCs) and induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) have been found to have a high potential as candidates for cardiac repair. Unlike embryonic stem cells, there are no ethical issues involved with these two cell types. Both can help in replacing the dead cells directly/indirectly. Even though initial pre‐clinical and clinical trials showed promise for using MSCs and iPSC‐CMs, but after transplantation, these cells were found to be rejected by the recipient immune system that led to deterioration of beneficial effects of stem cell based therapies. Therefore, we aim to decipher the mechanisms responsible for the rejection of the transplanted allogeneic MSCs and iPSC‐CMs by the host immune system. The immunoprivilige of allogeneic MSCs is preserved by absence of cell surface immune antigen, major histocompatibility complex (MHC)–II. We recently found that MHC‐II expression increased in rat and human MSCs after exposure to hypoxia or after transplantation in the infarcted rat heart. MHC‐II expression is regulated by a class II transactivator (CIITA). We found that hypoxic environment led to upregulation of ATPase subunit of 19S proteasome Sug1 and its binding to CIITA, that was associated with activation of CIITA and upregulation of MHC‐II expression. As a result, MSCs became immunogenic and were rejected by host immune system. Knocking down Sug1 in MSCs preserved immunoprivilege and prevented rejection of transplanted MSCs in the infarcted heart. In case of iPS cells, we found that after differentiation to cardiomyocytes there was a significant increase in the MHC‐II expression that was associated with upregulation of immunogenicity of iPSC‐CMs. Therefore, current study provides novel mechanisms of increase in immunogenicity of allogeneic MSCs and iPSC‐CMs. This study may help in facilitating a better planning for future MSCs or iPSC based clinical trials in cardiac patients.Support or Funding InformationCanadian Institutes of Health Research