TNF-alpha and hypoxia-induced paracrine secretion of rat bone marrow-mesenchymal stem cells for cardiac repair in Lewis rats post-ml
Bibliographic record
Abstract
Bone-marrow mesenchymal stem cell (BM-MSC) strategies have been suggested to play a crucial role in promoting the reparative process in ischemic hearts following a myocardial infarction (MI). However, poor viability and retention of transplanted cells in the harsh microenvironment remains as an obstacle. The paracrine hypothesis suggests that BM-MSCs secrete paracrine factors consisting of biologically active molecules that may work together to manipulate the microenvironment and trigger angiogenesis, cardioprotective, and homing properties at the site of infarct. The current study aims to understand the regulatory effects of Tumour Necrosis Factor-α (TNF-α) and hypoxia on rat BM-MSCs (rBM-MSC) and the angiogenic, migratory, cardioprotective, and reparative effects of its secretion which may, initiate and sustain the process of cardiac repair post MI. Secretome from rBM-MSC cultures treated/untreated with either conditioned rat cardiomyocyte medium (rCCM), TNF-α, and/or normoxia/hypoxia in various combinations were examined. Immunocytochemistry and western blot analyses confirmed the presence of the TNF-Receptors 1 and 2 (TNFR1/TNFR2) on the surface of rBM-MSCs, which indicates that TNF-α is able to bind to rBM-MSCs and initiate cell survival pathways through the TNFR2 pathway. Western blot analyses on rBM-MSC lysates treated with rCCM, TNF-α and hypoxia showed increased expression of TGF-β, FGF-2, VEGF-1, Myogenin, and Ang-2. Thus, indicating that in hypoxic conditions, TNF-α induces rBM-MSCs to secrete proteins that contribute to neovascularization; MSC/endothelial cell (EC) proliferation, migration or differentiation; and/or decreasing acute pro-inflammatory responses. Furthermore, the trans-well migration assay showed that the TNF-α Hypoxia-Induced secretome exhibits chemotactic properties, which may play a role in the migration of BM-MSCs to the site of infarct. The Annexin V apoptosis assay revealed that the TNF-α Hypoxia-Induced secretome treatment on rCMs under hypoxia does not show a statistically significant difference between the values for the control cells (rCMS with hypoxia only) and itself. Accordingly, there may be no significant difference in the number of apoptotic rCMs, as the presence of the TNF-α cytokine itself may be reducing the pro-survival effect of the secreted secretome. In vivo, induced infarcted Lewis rats treated with TNF-α Hypoxia-Induced secretome had a higher left ventricle fractional shortening (LVFS) than the control secretome (rCCM and hypoxia) treated rats, while trichrome staining revealed a decrease in the size of infarct. Hence, a higher LVFS and the decrease in the size of infarct in the TNF-α hypoxia-induced secretome treated Lewis rats show that myocardial preservation maybe occurring. Lastly, immunohistochemistry revealed increased expression of CD31 and Ki67 proteins near the area of infarct in the TNF-α Hypoxia-Induced secretome treated rats. The presence of the CD31 and Ki67 markers indicate an increase in vessel formation and proliferation at the site of infarct in TNF-α hypoxia-induced secretome treated rats. These findings suggest that the paracrine secretion of TNF-α and hypoxia preconditioned BM-MSCs may play a therapeutic role in cardiac repair post-MI.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.002 | 0.001 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 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 teacher head, 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".