Hypoxia-induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of mesenchymal stem cells

Abstract

Allogeneic mesenchymal stem cells (MSCs) are immunoprivileged and are being investigated in phase I and phase II clinical trials to treat different degenerative and autoimmune diseases. In spite of encouraging outcome of initial trials, the long-term poor survival of transplanted cells in the host tissue has declined the overall enthusiasm. Recent analyses of allogeneic MSCs based studies confirm that after transplantation in the hypoxic or ischemic microenvironment of diseased tissues, MSCs become immunogenic and are rejected by recipient immune system. The immunoprivilege of MSCs is preserved by absence or negligible expression of cell surface antigen, human leukocyte antigen (HLA)-DRα. We found that in normoxic MSCs, 26S proteasome degrades HLA-DRα and maintains immunoprivilege of MSCs. The exposure to hypoxia leads to inactivation of 26S proteasome and formation of immunoproteasome in MSCs, which is associated with upregulation and activation of HLA-DRα, and as a result, MSCs become immunogenic. Furthermore, inhibition of immunoproteasome formation in hypoxic MSCs preserves the immunoprivilege. Therefore, hypoxia-induced shift in the phenotype of proteasome from 26S toward immunoproteasome triggers loss of immunoprivilege of allogeneic MSCs. The outcome of the current study may provide molecular targets to plan interventions to preserve immunoprivilege of allogeneic MSCs in the hypoxic or ischemic environment.

The Proteasome Activator PA200/PSME4: An Emerging New Player in Health and Disease

“…One could envision that the hypoxic cells decrease PA200 to support the assembly of alternative proteasome complexes, including the PA28α/β- and PA28γ-associated immunoproteasomes, which are more efficient at coping with the oxidant-damaged proteins [ 77 , 81 ]. This notion is in line with the fact that hypoxia also induces the inducible immunoproteasome subunits [ 82 ]. Intriguingly, the view that PA200 and the inducible subunits β1i, β2i, and β5i are transcriptionally differentially regulated suggests that PA200 may not preferentially associate with the proteasomes carrying immunoproteasomes subunits.…”

Development of Fluorine‐Free Tantalum Carbide MXene Hybrid Structure as a Biocompatible Material for Supercapacitor Electrodes

“…Human Mesenchymal Stem Cells Culture: Human bone marrow derived MSC were purchased from Lonza (PT 2501, CA10064-080) and cultured in low-glucose DMEM (10 567 014, Gibco) according to previously published protocols. [58] Cell Proliferation Assay: Human iPSC-derived fibroblasts, cardiomyocytes, and NPCs were plated on 96-well plates and cocultured with or without the raw MAX phase and oxidized TTO composites at a concentration of 50 µg mL −1 for 24 h. Then, the cell proliferation was assessed using the WST-1 proliferation kit (K301, BioVision).…”

Hypoxia shapes the immune landscape in lung injury promoting inflammation persistence

“…Proteomic survey of the sorted classical monocytes from healthy controls and patients with ARDS further revealed a phenotypic switch, with a significant increase in the abundance of secretory granule content within the monocytes in ARDS (Figure 1k, l). This was observed across all ARDS samples, including patients with SARS-Cov2-associated ARDS, and was associated with altered expression of known hypoxia regulated proteins including SLC2A3 18 , IGFR2 19 , PSMD4 20 and FTL 21 . Taken together these data demonstrate that ARDS affects both the number and nature of monocytes.…”