Primary Cilia Disassembly Promotes Mammalian Cardiac Regeneration
Bibliographic record
Abstract
Myocardial infarction (MI) remains a leading cause of death worldwide due to the limited capacity of adult cardiac tissue to compensate for ischemic injury. For decades, models of complete heart regeneration in amphibians and fish were used to search for factors supporting cardiac regeneration post‐injury, but a mammalian model counterpart was not available. In 2011, Porrello et al. demonstrated that complete cardiac regeneration is possible during a neonatal window in mice, namely postnatal day 1 (P1). However, the mammalian heart loses its regenerative potential shortly after birth by P7. The ability of proliferating cardiomyocytes to replace damaged tissue is intimately linked with the formation of new supportive blood vessels. In lower vertebrates, the epicardium is the cellular source of the regenerated vasculature. Epicardial cells are able to recapitulate their embryonic profile and undergo the process of epithelial‐to‐mesenchymal transition (EMT) to contribute to angiogenesis. Novel evidence from our laboratory indicates that genes related to EMT are upregulated post‐MI more so in the P1 mouse (regenerative) than the P7 mouse (non‐regenerative). Primary cilia are small microtubule based sensory organelles that coordinate multiple EMT signaling pathways during embryonic coronary artery formation. After receptors on primary cilia receive EMT signals, the cilia disassemble. The absence of ciliary function in the embryonic mouse heart then induces EMT. The aim of this study was to investigate the ability of stimulation of cilia disassembly to promote EMT and angiogenesis for cardiac regeneration post‐MI in neonatal mice. A reproducible model of neonatal MI has recently been established in our laboratory (unpublished). MI was induced in P7 C57BL/6 neonatal mice followed by intramyocardial injection of an adenoviral construct containing short hairpin RNA (shRNA) for intraflagellar transport 88 (Ad‐Ift88), a protein vital to ciliary function. Injection of an adenoviral construct containing the green fluorescent protein (Ad‐GFP) served as a control. Hearts were collected 21 days post‐MI (P28) and infarct size was measured after Masson's trichrome staining. Ad‐Ift88 treatment reduced scar formation observed at this time point, indicating up‐regulation of mechanisms supporting cardiac regeneration. To determine the effects of ciliary function on EMT in epicardial cells, an in vitro model of epithelial‐to‐mesenchymal transition was used. Embryonic hearts were harvested at E12.5 and plated epicardial side down on a collagen gel to allow outgrowth and transition of epicardium derived cells (EPDCs). The number of spindle shaped cells was counted 1, 3, 5 and 7 days after treatment to determine effects on EMT. Treatment with Ad‐Ift88 augmented EPDC transition as compared to Ad‐GFP controls at all four time points. These results indicate that promoting ciliary disassembly with shRNA for the Ift88 transport protein promotes cardiac regeneration. This study is the first to show that inhibition of Ift88 promotes EMT of epicardial cells, which may provide supportive vasculature for cardiac regeneration in mammals. Support or Funding Information This study was supported by an operating grant from the Canadian Institutes of Health Research (CIHR) to Q.F. (grant #MOP‐119600).
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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) | 0.001 | 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 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".