Abstract 15222: Cycloxygenase 2 Preserves Immunoprivilege of Allogeneic Mesenchymal Stem Cells in the Ischemic Heart
Introduction: Bone marrow derived allogeneic mesenchymal stem cells (MSCs) from young healthy donors are immunoprivileged and are considered to be excellent cell type for cardiac regeneration. The outcome of preclinical studies and initial clinical trials suggested that transplanted cells were able to improve cardiac function following a myocardial injury. However the beneficial effects were not persistent, also the long term fate of transplanted cells in these studies was not determined. We recently reported that MSCs became immunogenic late after implantation in the ischemic heart and were rejected, resulting in progressive deterioration of heart function. The present study reveals the mechanisms responsible for this post-transplantation immune switch in MSCs.
Methods/Results: MSC immunoprivilege was found to be mediated by prostaglandin E2 (PGE2), the levels of PGE2 decreased in MSCs after exposure to hypoxia or ischemic conditions. PGE2 is synthesized in the cells by sequential oxidation of arachidonic acid by cyclooxygenase 2 (COX2). The levels of COX2 decreased in hypoxic MSCs which was associated with loss of immunoprivilege, as we observed increased cytotoxicity in hypoxic MSCs caused by allogeneic T cells in the in vitro co-culture. Furthermore, blocking COX2 pathway in normoxic MSCs increased their immunogenicity. MSCs immunoprivilege is established by the absence of major histocompatibility complex class II (MHC-II) molecules. Our data suggest that MHC-II expression increased in rat MSCs after exposure to hypoxia. PGE2 treatment of hypoxic MSCs decreased MHC-II expression and preserved their immunoprivilege. Furthermore, in a rat model of myocardial infarction, maintaining PGE2 levels in the infarct area with a biodegradable hydrogel, prevented the rejection of transplanted allogeneic MSCs (3х106 cells/rat) and improved cardiac function.
Conclusions: COX2 prevents the rejection of transplanted allogeneic MSCs in the ischemic heart by maintaining the levels of PGE2 that further regulates MHC-II levels on MSC surface and preserves their immunoprivilege. The outcome of these studies may help in interpreting the results of ongoing allogeneic MSCs based clinical trials in cardiac patients.
Author Disclosures: N. Sareen: None. E. Abu-El Rub: None. G. Sequiera: None. S. Saravanan: None. M. Moudgil: None. S. Dhingra: None.
- © 2016 by American Heart Association, Inc.