Hypoxia‐Induced Inactivation of 26S Proteasome Increases Immunogenicity of Allogeneic Mesenchymal Stem Cells
Bibliographic record
Abstract
Allogeneic (donor derived) mesenchymal stem cells (MSCs) derived from bone marrow are in phase I and II clinical trials for cardiac regeneration. Even though the outcome of allogeneic MSCs based animal studies and initial clinical trials was encouraging, the overall enthusiasm of lately has come down. This is due to poor survival of transplanted cells in the recipient heart. The recent reports on allogeneic MSCs based studies found a switch in the phenotype of transplanted cells from immunoprivileged to immunogenic state that led to rejection of cells by host immune system. In the current study, we discovered a novel mechanism of immune switch in MSCs. Our studies demonstrate that hypoxia/or ischemic environment induces an immune shift in MSCs from immunoprivileged to immunogenic state. The immunoprivilege of MSCs is preserved by absence of major histocompatibility complex class II (MHC‐II) molecules. We found that 26S proteasome‐mediated degradation of MHC‐II prevents its expression on cell surface in 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 increased immunogenicity of MSCs. Furthermore, hypoxia‐induced downregulation of a chaperon protein HSP90α is responsible for inactivation of 26S proteasome. Maintaining HSP90α levels in hypoxic MSCs prevented 26S inactivation and preserved the immunoprivilege of MSCs. Therefore, hypoxia‐induced defects in 26S proteasome assembly causes loss of immunoprivilege of allogeneic MSCs. Maintaining 26S proteasome activity in MSCs preserves immunoprivilege and prevents rejection of allogeneic stem cells in the heart. Support or Funding Information Canadian Institute of Health Research This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".