Abstract 11282: Maintaining Prostaglandin E2 Levels Prevents Rejection of Implanted Allogeneic Mesenchymal Stem Cells and Restores Post-Infarction Ventricular Function
Introduction: Allogeneic mesenchymal stem cells (MSCs) are immune privileged early after cardiac implantation and improved heart function in both preclinical and clinical studies. We recently reported that allogeneic MSCs differentiated late after their implantation, lost their immune privilege, and were rejected, resulting in progressive deterioration of heart function. The present study reveals the mechanisms responsible for this post-differentiation immune switch in MSCs and suggests a new treatment to maintain immune privilege and preserve heart function.
Methods/Results: MSC immune privilege was found to be mediated by prostaglandin E2 (PGE2)-induced endogenous IL-10 production, which sustained the secretion of two critical chemokines, CCL12 and CCL5, by MSCs in an autocrine manner. These chemokines induced T cell attraction to the MSCs, suppressed T cell proliferation, and stimulated the production of T regulatory (CD4+CD25+) cells. MSCs treated with 5-azacytidine for 24 h differentiated into myogenic cells after 2 weeks (increased myogenic-specific α- and β-myosin heavy chain expression). MSC differentiation was associated with decreased PGE2 levels and the loss of immune privilege (increase in T cell-mediated cytotoxicity). Treatment of differentiated MSCs with PGE2 maintained IL-10 and chemokine levels, decreased T cell-mediated cytotoxicity, suppressed T cell proliferation, and increased the production of T regulatory cells. In a rat myocardial infarction (MI) model, allogeneic MSCs (3×106 cells/rat), with or without a biodegradable hydrogel that slowly released PGE2, were injected into the infarct region. Five weeks later, the allogeneic MSCs were rejected in the control group (no PGE2), but in the PGE2-treated group, 35% of the transplanted cells survived and heart function was significantly improved.
Conclusions: Immune privilege of allogeneic MSCs was maintained by PGE2-induced IL-10 production, which sustained the MSC secretion of CCL12 and CCL5. MSC differentiation resulted in decreased PGE2, reduced ability to attract and suppress cytotoxic leukocytes, and the loss of immune privilege. Maintaining PGE2 levels (with a hydrogel) preserved immune privilege and the restored cardiac function after an MI.
- © 2012 by American Heart Association, Inc.