Abstract 15302: Genetic Enhancement of Insulin-Like Growth Factor-1 in Human Cardiac Stem Cells Prevents Cell Death and Enhances Ischemic Myocardial Repair
Bibliographic record
Abstract
Insulin-like growth factor (IGF-1) activates pro-survival pathways and improves post ischemic cardiac function but this key cytokine is not expressed by ex vivo proliferated human cardiac stem cells (CSCs). Here, we explore the influence of an IGF-1 enhanced paracrine signature on CSC-mediated cardiac repair. Methods/Results: To rationalize the timing of IGF-1 delivery to infarcted myocardium, the expression of the IGF-1 receptor (IGF-1R) transcript was screened in myocardial samples from C57 mice taken 1, 7, 14 and 21 days after experimental myocardial infarction (MI). Seven days after LAD ligation, IGF-1R expression was increased by 1.4±0.7 and 3.0±0.8 fold in the infarct and border zones (p≤0.05) and remained elevated throughout the sampling period. Based on these data, human CSCs underwent lentivirus-mediated somatic gene transfer to overexpress human IGF-1 (CSC IGF-1 ) or the GFP reporter alone (CSC GFP ). Genetic engineering enhanced the IGF-1 content within hypoxic conditioned media by 8.1±1.9 fold (p=0.01) with no discernible effects on population doubling time (1.1±0.3 vs. 1.2±0.1 days, p=ns). With the exception of enhanced IGF-1, a proteomic array of 59 cardioprotective/pro-angiogenic cytokines demonstrated that CSC IGF-1 engineering improved the secretion of additional cytokines compared to CSC GFP . Culture of CSC IGF-1 within conditions designed to mimic the ischemic border zone improved proliferation and reduced the expression of annexin V compared to CSC GFP or non-transduced CSCs (proliferation: 30±13% vs. -14±15% or -19±12% change in cell numbers, p≤0.05; annexin V: 30±6% vs. 74±9% or 77±1%, respectively; p≤0.05). These results may be partially explained through the enhancement of downstream activators within the AKT, ERK and MAPK pro-survival pathways (p≤0.05 vs. CSC GFP ). Intra-myocardial injection of CSC IGF-1 into immunodeficient mice one week after MI enhanced cardiac repair as compared to CSC GFP and vehicle controls. (echocardiographic left ventricular ejection fraction 28 days post LAD ligation: 41±1% vs. 37±1% or 25±1%, respectively; p Conclusions: Paracrine engineering of CSCs to over-express IGF-1 boosts CSC resistance to hypoxia and improves cell-mediated cardiac repair.
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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".