Transcriptional remodeling of cardiomyocytes and fibroblasts during post-myocardial infarction recovery.

Myocardial infarction (MI) results from reduced coronary blood flow, leading to oxygen deprivation and impaired systolic and diastolic function, which increases the risk of cardiac arrhythmias. Various cardiac cell types respond to this stress to preserve heart function, but the precise, cell-type-specific mechanisms remain poorly understood. To investigate these responses, we performed single-nucleus RNA sequencing (snRNA-seq) on left ventricular tissue from mouse hearts at baseline (Day 0) and at 1 and 4 weeks post-MI. This enabled us to characterize transcriptional changes across major cardiac cell types. We observed significant shifts in the transcriptional states of cardiomyocytes (CMs) and fibroblasts (FBs) cell populations following MI. CMs showed a major transcriptional modulation from healthy to diseased state during early chronic phase of post-MI, however, the recovery phenotype was observed during the late chronic phase, suggesting a natural compensatory response of CMs against the ischemic stress. FBs exhibited dynamic transcriptional changes consistent with roles in post-MI healing and fibrosis. In addition, inferred alterations in cell-cell communication networks highlighted changes in intercellular signaling pathways, shedding light on disrupted crosstalk in the injured heart. Together, our findings provide a comprehensive transcriptional landscape of cardiac cell populations, especially CMs and FBs, following MI and identify potential molecular targets for therapeutic intervention.