Defining the molecular underpinnings controlling cardiomyocyte proliferation
Bibliographic record
Abstract
Shortly after birth, mammalian cardiomyocytes (CM) exit the cell cycle and cease to proliferate. The inability of adult CM to replicate renders the heart particularly vulnerable to injury. Restoration of CM proliferation would be an attractive clinical target for regenerative therapies that can preserve contractile function and thus prevent the development of heart failure. Our review focuses on recent progress in understanding the tight regulation of signaling pathways and their downstream molecular mechanisms that underly the inability of CM to proliferate in vivo. In this review, we describe the temporal expression of cell cycle activators e.g., cyclin/Cdk complexes and their inhibitors including p16, p21, p27 and members of the retinoblastoma gene family during gestation and postnatal life. The differential impact of members of the E2f transcription factor family and microRNAs on the regulation of positive and negative cell cycle factors is discussed. This review also highlights seminal studies that identified the coordination of signaling mechanisms that can potently activate CM cell cycle re-entry including the Wnt/Ctnnb1, Hippo, Pi3K-Akt and Nrg1-Erbb2/4 pathways. We also present an up-to-date account of landmark studies analyzing the effect of various genes such as Argin, Dystrophin, Fstl1, Meis1, Pitx2 and Pkm2 that are responsible for either inhibition or activation of CM cell division. All these reports describe bona fide therapeutically targets that could guide future clinical studies toward 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 | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".