Abstract Body: Adult mammalian cardiomyocytes (CMs) have extremely limited proliferative capacity, and loss of CMs after myocardial infarction (MI) leads to fibrotic scar formation and progression to heart failure. In contrast, neonatal mouse hearts can efficiently regenerate lost myocardium through proliferation of pre-existing CMs. This regenerative capacity is lost by postnatal day 7 (P7), resulting in permanent scar formation like the adult heart. The transcriptional regulators governing the regenerative competence of the neonatal heart remain poorly defined. By single-nucleus RNA sequencing, we previously identified a proliferative population of cardiomyocytes, referred to as CM4, that exhibits robust cell cycle activity after MI in regenerative neonatal hearts. Transcriptomic analysis revealed that Nuclear Factor I B (NFIB) is highly enriched in the CM4 population and sharply upregulated in CM4 cells after MI, suggesting a potential role during heart regeneration.
NFIB expression in the heart declines progressively after birth, coinciding with the loss of the regenerative capacity. To determine whether NFIB regulates neonatal cardiomyocyte proliferation, we overexpressed NFIB in cultured neonatal rat ventricular cardiomyocytes (NRVMs), which showed increased cardiomyocyte proliferation. To further evaluate its function in vivo, we delivered NFIB to wild-type mice at P4 using adeno-associated virus serotype 9 and performed permanent ligation of the left anterior descending coronary artery (LAD ligation) to induce MI at P8. Following MI, mice injected with AAV9-NFIB showed significantly reduced infarct scar size and improved preservation of myocardial tissue with attenuated adverse remodeling, compared with control AAV9 treated mice. Functional measurements demonstrated improved cardiac performance relative to control animals. We are further dissecting the molecular mechanisms by which NFIB enhances cardiac function and reduces scar formation. These results demonstrate that NFIB promotes recovery of cardiac function and limits fibrotic remodeling following MI in neonatal hearts, identifying NFIB as a transcriptional regulator of neonatal heart regeneration and a potential therapeutic target for adult heart upon injury.