Abstract 135: Hypoxia Induced Defects in 26S Proteasome Machinery Causes Loss Of Immunoprivilege of Allogeneic Mesenchymal Stem Cells
Bibliographic record
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)
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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) | 0.005 | 0.001 |
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".