Hypoxia-induced 26S proteasome dysfunction increases immunogenicity of mesenchymal stem cells

Abstract

Bone marrow-derived allogeneic (donor derived) mesenchymal stem cells (MSCs) are immunoprivileged and are considered to be prominent candidates for regenerative therapy for numerous degenerative diseases. Even though the outcome of initial allogeneic MSCs based clinical trials was encouraging, the overall enthusiasm, of late, has dimmed down. This is due to failure of long-term survival of transplanted cells in the recipient. In fact, recent analyses of allogeneic MSC-based studies demonstrated that cells after transplantation turned immunogenic and were subsequently rejected by host immune system. The current study reveals a novel mechanism of immune switch in MSCs. We demonstrate that hypoxia, a common denominator of ischemic tissues, induces an immune shift in MSCs from immunoprivileged to immunogenic state. The immunoprivilege of MSCs is preserved by downregulation or the absence of major histocompatibility complex class II (MHC-II) molecules. We found that 26S proteasome-mediated intracellular degradation of MHC-II helps maintain the absence of MHC-II expression on cell surface in normoxic MSCs and preserves their immunoprivilege. The exposure to hypoxia leads to dissociation of 19S and 20S subunits, and inactivation of 26S proteasome. This prevented the degradation of MHC-II and, as a result, the MSCs became immunogenic. Furthermore, we found that hypoxia-induced decrease in the levels of a chaperon protein HSP90α is responsible for inactivation of 26S proteasome. Maintaining HSP90α levels in hypoxic MSCs preserved the immunoprivilege of MSCs. Therefore, hypoxia-induced inactivation of 26S proteasome assembly instigates loss of immunoprivilege of allogeneic mesenchymal stem cells. Maintaining 26S proteasome activity in mesenchymal stem cells preserves their immunoprivilege.

Cross talk between 26S proteasome and mitochondria in human mesenchymal stem cells’ ability to survive under hypoxia stress

“…No study so far has revealed the mechanistic medium that can solve the puzzle regarding the ability of MSCs to handle moderate hypoxia, but not the severe hypoxia. Currently, it has been discovered that 26S proteasome turned to be dysfunction machinery causing the rejection of MSCs in ischemic environment [1]. In this study, our results demonstrated that 26S proteasome machinery is the key to resolving this perplexing enigma of why MSCs tolerate and survive moderate hypoxia not severe one.…”

Hypoxia‐induced increase in Sug1 leads to poor post‐transplantation survival of allogeneic mesenchymal stem cells

“…The initial assumptions that allogeneic MSC preparations represent “one‐size‐fits‐all” and “off‐the‐shelf” products were originated from the facts that MSCs were immunoprivileged. However, recent data from preclinical studies and clinical trials strongly suggest that even though allogeneic MSCs display immunoprivilege under in vitro conditions, late after transplantation in the host microenvironment, MSCs become immunogenic and provoke an immune response resulting in rejection 12,24,56 . We found that hypoxic or ischemic environment in the host tissue leads to the upregulation of CIITA and cell surface immune antigen MHC‐II in rat and human MSCs.…”

“…MSCs were isolated from the femurs and tibias of Sprague Dawley rats as described in our recent studies. 12,20,21 Bone marrow was flushed with Dulbecco's Modified Eagle's Medium (DMEM) supplemented with 15% fetal bovine serum, 100 units/mL of penicillin G, and 0.1 mg/mL of streptomycin. The cells were plated and cultured in DMEM overnight.…”

“…10,11 Increasing evidence now confirm that though initially immunoprivileged, the MSCs eventually become immunogenic after transplantation in the stressful environment of diseased tissues and are rejected by the host immune system. [12][13][14][15][16] The poor survival and decline in the MSCs-mediated benefits over time has dampened the enthusiasm regarding allogeneic MSCs-based regenerative therapies. In this regard, several studies have reported the mechanisms of immunoprivilege of MSCs and MSCs-mediated beneficial effects.…”

Substantial Overview on Mesenchymal Stem Cell Biological and Physical Properties as an Opportunity in Translational Medicine

“…A recent study had explained some of the controversies as the authors demonstrated that exposure to hypoxia leads to dissociation of 19S and 20S subunits and inactivation of 26S proteasome which prevents degradation of MHC-II and, as a result, MSC become immunogenic. It was concluded that hypoxia-induced inactivation of 26S proteasome assembly instigates loss of immunoprivilege of allogeneic mesenchymal stem cells while maintaining 26S proteasome activity in mesenchymal stem cells preserves their immunoprivilege [72].…”