Abstract 15547: Restoration of Interleukin-10 Levels in Differentiated Mesenchymal Stem Cells Preserves their Immunoprivilege in Allogeneic Implantation and Restores Post-Infarction Cardiac Function
Bibliographic record
Abstract
Introduction: Young healthy donor mesenchymal stem cells (MSCs) are very good candidates for heart repair as they are immunoprivileged and have excellent regenerative capacity. We showed that allogeneic MSCs reduced host immune response and survived early after injection into the ischemic myocardium, but later lost their immunoprivilege and were rejected. Here we show the mechanisms responsible for this immune switch and suggest a way to preserve immunoprivilege and heart function. Methods/Results: Allogeneic MSCs were co-cultured with lymphocytes and allo-immune responses were assessed. MSC immunoprivilege was mediated by the immunosuppressive cytokine interleukin-10 (IL-10), as the level of lymphocyte-mediated cytotoxicity was significantly greater for IL-10 knock-out MSCs compared to wild-type. Myogenic differentiation of MSCs led to decreased IL-10 levels and loss of immunoprivilege. Adenovirus-mediated IL-10 gene transfer to differentiated MSCs (DMSCs) decreased cytotoxicity and preserved immunoprivilege. In a rat MI model, allogeneic MSCs transplanted into the infarct region were mostly rejected by 5 weeks. Maintaining IL-10 levels in MSCs prevented anti-donor antibodies against transplanted MSCs and increased cell survival. IL-10 over-expressing MSCs also improved %FS and LV dimensions compared to media injected controls. IL-10 gene therapy in allogeneic MSCs also prevented scar thinning. To investigate further, we co-cultured allogeneic MSCs with lymphocytes for 72h and found that undifferentiated MSCs promoted immune suppression by decreasing lymphocyte proliferation and increasing production of regulatory T cells (Tregs), whereas DMSCs did not inhibit lymphocyte proliferation or induce Treg production. IL-10 over-expression in DMSCs preserved immunoprivilege by decreasing lymphocyte proliferation and by increasing Treg production. Conclusion: IL-10 mitigated the recipient’s allo-immune responses against transplanted MSCs. MSC differentiation led to decreased IL-10, reduced ability to suppress cytotoxic lymphocytes, and loss of immune privilege. Maintaining IL-10 levels preserved immune privilege, increased survival of transplanted MSCs and restored cardiac function after MI.
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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) | 0.001 | 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 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".