Abstract 135: Hypoxia Induced Defects in 26S Proteasome Machinery Causes Loss Of Immunoprivilege of Allogeneic Mesenchymal Stem Cells

Abstract

The poor survival of transplanted allogeneic mesenchymal stem cells (MSCs) in the recipient heart has dampened the overall enthusiasm of allogeneic MSCs based clinical trials. Outcome of recent studies suggests that the phenotype of transplanted cells changes from immunoprivileged to immunogenic state that leads to rejection of implanted cells by host immune system. In this study, we present a novel mechanism of immune switch in MSCs. We found that hypoxia/or ischemic environment shifts immunological landscape of MSCs from immunoprivileged to immunogenic state. The immunoprivilege of MSCs is preserved by absence of major histocompatibility complex class II (MHC-II) molecule. Our studies demonstrate that 26S proteasome-mediated degradation of MHC-II prevents its expression on cell surface in MSCs and preserves their immunoprivilege. The exposure to hypoxia results in dissociation of 19S and 20S subunits, and inactivation of 26S proteasome. This promotes accumulation of MHC-II and increases immunogenicity of MSCs. We also found that a chaperon protein HSP90α is responsible for 26S proteasome activity in normoxic MSCs. The level of HSP90α decreases in hypoxic MSCs that leads to increase in immunogenicity. Maintaining HSP90α levels in hypoxic MSCs prevents 26S inactivation and preserves immunoprivilege of MSCs. Therefore, hypoxia-induced defects in 26S proteasome assembly causes loss of immunoprivilege of allogeneic MSCs. Preserving 26S proteasome activity in MSCs maintains immunoprivilege and prevents rejection of allogeneic MSCs in the heart. (This work was supported by CIHR)