Allogeneic stem cell therapy for cardiac repair and host immune response
Bibliographic record
Abstract
Bone marrow derived allogeneic (unrelated donor) mesenchymal stem cells (MSCs) and induced pluripotent stem cell‐derived cardiomyocytes (iPSC‐CMs) have been found to have a high potential as candidates for cardiac repair. Unlike embryonic stem cells, there are no ethical issues involved with these two cell types. Both can help in replacing the dead cells directly/indirectly. Even though initial pre‐clinical and clinical trials showed promise for using MSCs and iPSC‐CMs, but after transplantation, these cells were found to be rejected by the recipient immune system that led to deterioration of beneficial effects of stem cell based therapies. Therefore, we aim to decipher the mechanisms responsible for the rejection of the transplanted allogeneic MSCs and iPSC‐CMs by the host immune system. The immunoprivilige of allogeneic MSCs is preserved by absence of cell surface immune antigen, major histocompatibility complex (MHC)–II. We recently found that MHC‐II expression increased in rat and human MSCs after exposure to hypoxia or after transplantation in the infarcted rat heart. MHC‐II expression is regulated by a class II transactivator (CIITA). We found that hypoxic environment led to upregulation of ATPase subunit of 19S proteasome Sug1 and its binding to CIITA, that was associated with activation of CIITA and upregulation of MHC‐II expression. As a result, MSCs became immunogenic and were rejected by host immune system. Knocking down Sug1 in MSCs preserved immunoprivilege and prevented rejection of transplanted MSCs in the infarcted heart. In case of iPS cells, we found that after differentiation to cardiomyocytes there was a significant increase in the MHC‐II expression that was associated with upregulation of immunogenicity of iPSC‐CMs. Therefore, current study provides novel mechanisms of increase in immunogenicity of allogeneic MSCs and iPSC‐CMs. This study may help in facilitating a better planning for future MSCs or iPSC based clinical trials in cardiac patients. Support or Funding Information Canadian Institutes of Health Research
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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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 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".