Abstract 15547: Restoration of Interleukin-10 Levels in Differentiated Mesenchymal Stem Cells Preserves their Immunoprivilege in Allogeneic Implantation and Restores Post-Infarction Cardiac Function
Introduction: Young healthy donor mesenchymal stem cells (MSCs) are very good candidates for heart repair as they are immunoprivileged and have excellent regenerative capacity. We showed that allogeneic MSCs reduced host immune response and survived early after injection into the ischemic myocardium, but later lost their immunoprivilege and were rejected. Here we show the mechanisms responsible for this immune switch and suggest a way to preserve immunoprivilege and heart function.
Methods/Results: Allogeneic MSCs were co-cultured with lymphocytes and allo-immune responses were assessed. MSC immunoprivilege was mediated by the immunosuppressive cytokine interleukin-10 (IL-10), as the level of lymphocyte-mediated cytotoxicity was significantly greater for IL-10 knock-out MSCs compared to wild-type. Myogenic differentiation of MSCs led to decreased IL-10 levels and loss of immunoprivilege. Adenovirus-mediated IL-10 gene transfer to differentiated MSCs (DMSCs) decreased cytotoxicity and preserved immunoprivilege. In a rat MI model, allogeneic MSCs transplanted into the infarct region were mostly rejected by 5 weeks. Maintaining IL-10 levels in MSCs prevented anti-donor antibodies against transplanted MSCs and increased cell survival. IL-10 over-expressing MSCs also improved %FS and LV dimensions compared to media injected controls. IL-10 gene therapy in allogeneic MSCs also prevented scar thinning. To investigate further, we co-cultured allogeneic MSCs with lymphocytes for 72h and found that undifferentiated MSCs promoted immune suppression by decreasing lymphocyte proliferation and increasing production of regulatory T cells (Tregs), whereas DMSCs did not inhibit lymphocyte proliferation or induce Treg production. IL-10 over-expression in DMSCs preserved immunoprivilege by decreasing lymphocyte proliferation and by increasing Treg production.
Conclusion: IL-10 mitigated the recipient’s allo-immune responses against transplanted MSCs. MSC differentiation led to decreased IL-10, reduced ability to suppress cytotoxic lymphocytes, and loss of immune privilege. Maintaining IL-10 levels preserved immune privilege, increased survival of transplanted MSCs and restored cardiac function after MI.
Author Disclosures: S. Dhingra: None. J. Wu: None. S. Li: None. J. Guo: None. J. Hu: None. R.D. Weisel: None. R. Li: None.
- © 2014 by American Heart Association, Inc.