Identification of a novel transcriptional factor repressing cardiomyocyte renewal in postnatal growth and injury repair
Description: Current available clinical treatments greatly reduced the acute mortality of myocardial infarction. However, lost cardiomyocytes during myocardial injury still cannot be replenished, leading to a steady increase of heart failure patients. In contrast, adult zebrafish and newborn mammals are capable of robust cardiac regenerative repair. This process has been shown to rely on proliferation of preexisting cardiomyocytes after injury. In rodents, such an ability is lost within the first week after birth when the majority of cardiomyocytes undergo permanent cell-cycle arrest. The physiological triggers of this transition remain largely unknown. Intriguingly, our recently published work suggests that activation of thermogenic pathways during the acquisition of endothermy in ontogeny and phylogeny may cause a loss of cardiomyocyte proliferative and regenerative capacity. Following this direction, we discover that increases of postnatal neurohormonal activities associated with thermogenesis drive cardiomyocyte cell-cycle exit, at least in part through stimulating the cardiac expression of a previously unappreciated transcription factor B-cell lymphoma 6 (Bcl6). Bcl6 is the second most up-regulated transcription factor (19 folds) in the postnatal mouse heart although its function in cardiomyocytes is largely unknown. We generated mutant mice lacking Bcl6 in cardiomyocytes and found enhanced cardiomyocyte proliferation during postnatal development and after myocardial infarction injury in the adult. In this proposal, we will investigate how Bcl6 expression is activated by neurohormonal pathways, whether deletion of Bcl6 delays cardiomyocyte cell-cycle withdrawal during postnatal growth, and whether inactivation of Bcl6 promotes heart regeneration in adult mice. Understanding the regulation and function of Bcl6 in the heart will yield significant insights into the genetic circuitry governing cardiac regenerative potential loss, and may offer novel treatment strategies to enhance heart regenerative repair in adult mammals.
Funder: American Heart Association
Amount: $300,000
Funding type: research
Funder scheme: Transformational Project Award
Start date: 2021-01-01
End date: 2023-12-31
Investigators: Guo Huang, Guo Huang
Institution: The Regents of the University of California, San Francisco
Funded outputs count: 3
Funder award ID: 20TPA35500000
OpenAlex ID: G2913992684