Abstract
The unique immunomodulatory properties of bone marrow derived allogeneic mesenchymal stem cells (MSCs) make them excellent candidate cell type for clinical applications. The outcome of preclinical studies and initial clinical trials suggested that after transplantation to the infarcted heart, allogeneic MSCs were able to improve cardiac function. However the long term fate of transplanted cells in these studies was not determined. We recently reported that allogeneic MSCs improved heart function after implantation in the infarcted heart. However, late after implantation, transplanted cells lost their immunoprivilege, and were rejected. Therefore we started extensive investigations to study the mechanisms of rejection. Our data demonstrate that MSC immunoprivilege was found to be mediated by prostaglandin E2 (PGE2), the levels of this soluble factor decreased in rat MSCs after exposure to hypoxia/ischemic conditions which was associated with loss of immunoprivilege and rejection of transplanted allogeneic MSCs. We observed increased cytotoxicity in hypoxic MSCs caused by allogeneic T cells in the in vitro co-culture. Furthermore, blocking PGE2 biosynthesis in normoxic MSCs increased the immunogenicity of MSCs. MSCs immunoprivilege is reported to be established by the absence of major histocompatibility complex class II (MHC-II) molecules. Our data suggest that MHC-II expression increased in MSCs after exposure to hypoxia. PGE2 treatment of hypoxic MSCs decreased MHC-II expression and preserved their immunoprivilege. In a rat myocardial infarction (MI) model, maintaining PGE2 levels with a biodegradable, temperature sensitive hydrogel in the infarct region prevented rejection of transplanted allogeneic MSCs and restored cardiac function after five weeks of cell transplantation. In conclusion, immunoprivilege of allogeneic MSCs was maintained by PGE2 mediated regulation of MHC-II levels, exposure to hypoxia/ischemia decreased PGE2 and increased MHC-II levels that was associated with loss of immunoprivilege and rejection of MSCs. Maintaining PGE2 levels preserved immunoprivilege and restored cardiac function after an MI.
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