Loss of lncRNA <i>H19</i> impairs neonatal cardiac regeneration

Cardiac regeneration represents a major unmet goal in cardiovascular medicine. While adult mammalian hearts have very limited capacity to regenerate after injury, newborn mouse hearts can fully restore myocardial structure and function following ischemic damage. This remarkable regenerative ability is rapidly lost within the first postnatal week, but the molecular mechanisms remain poorly understood. Long non-coding RNAs (lncRNAs) have emerged as important regulators of tissue repair and regeneration. Therefore, we aimed to identify lncRNAs involved in neonatal cardiac regeneration and to investigate the function of a candidate lncRNA in regenerating mouse hearts. RNA-sequencing of postnatal day 1 (P1) and P7 mouse hearts revealed approximately 700 significantly differentially expressed lncRNAs. Mapping three neonatal heart RNA-sequencing datasets identified the conserved lncRNA H19 as a major nodal point. To assess its potential regenerative function, permanent left anterior descending artery (LAD) ligation surgeries were performed in P1 H19 knockout (KO) and wild type (WT) mice. Myocardial infarction (MI) induction and cardiac function were evaluated by echocardiography. Hearts were harvested for molecular biological and histopathological analyses. Unlike H19WT mice, H19KO neonates failed to recover cardiac function after MI. While H19WT hearts showed no fibrotic scarring and complete cardiac regeneration, H19KO hearts exhibited increased collagen and Mmp9 expression one-week post-MI and exhibited fibrotic healing at one and two weeks post-MI. Additionally, H19KO mice displayed increased proliferation of non-cardiomyocytes and altered immune cells when compared to H19WT mice, indicating substantially impaired cardiac regeneration. In conclusion, H19 is essential for complete cardiac regeneration after MI in neonatal mice.