Effect of hypoxic/ischemic environment on the immunoprivilege of allogeneic mesenchymal stem cells
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Date
2020-05
Authors
Abu-El-Rub, Ejlal
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Abstract
Bone marrow derived allogeneic (donor derived) mesenchymal stem cells (MSCs) are immunoprivileged and are considered to be the prominent cell type for regenerative therapy for numerous diseases including cardiovascular disorders. Even though the outcome of initial allogeneic MSCs based clinical trials in cardiac patients was encouraging, the overall enthusiasm has diminished lately due to failure of long-term survival of transplanted cells in the recipient heart. In fact, recent analyses of allogeneic MSCs based studies demonstrated that transplanted cells in the ischemic heart become immunogenic and were subsequently rejected by the host immune system. We demonstrate that hypoxia, a common denominator of ischemic tissues including the infarcted heart, induces an immune shift in MSCs from immunoprivileged to immunogenic state. The immunoprivilege of MSCs is preserved by downregulation or absence of major histocompatibility complex class II (MHC-II) molecules. We found that in rat and human MSCs, 26S proteasome-mediated intracellular degradation of MHC-II helps maintain the absence of MHC-II expression on the cell surface in normoxic cells and preserves their immunoprivilege. The exposure to hypoxia leads to dissociation of 19S and 20S subunits, and inactivation of 26S proteasome. This dissociation prevents the degradation of MHC-II, and as a result the MSCs become immunogenic under hypoxic conditions. Furthermore, we found that exposure to hypoxia induces an increase in the levels of Sug1, which is the ATPase subunit of 19S proteasome. The upregulation of Sug1 in hypoxic MSCs was associated with the activation of Class II Transactivator “CIITA” which is a master regulator of transcription initiation of MHC-II. We found that knocking down Sug1 in MSCs preserved their immunoprivilege in vitro (rat and human MSCs) as well as in vivo (rat MSCs) in a rat model of myocardial infarction. Interestingly, our investigations also revealed that after exposing MSCs to a hypoxic stress, 26S proteasome is converted into a highly immunogenic complex called the immunoproteasome. Hypoxia induced formation of the immunoproteasome in MSCs was further associated with maturation and activation of MHC-II and loss of immunoprivilege. Taken together these findings provide a novel insight into the molecular events responsible for hypoxia induced shift in the phenotype of MSCs from immunoprivileged to immunogenic state. More importantly these studies also provide targets to preserve immunoprivilege of MSCs under hypoxic or ischemic conditions.
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Keywords
Mesenchymal Stem cells, Immunogenicity, Hypoxia, MHC-II