Primary Cilia Disassembly Promotes Mammalian Cardiac Regeneration
Notice bibliographique
Résumé
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 A reproducible model of neonatal MI has recently been established in our laboratory (unpublished).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).
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,001 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».