Abstract 147: Screening for Developmental and Injury-Induced Genes That Facilitate Heart Regeneration

Abstract

The adult mammalian heart has a limited capacity to regenerate upon injury, such as myocardial infarction (MI). MI in adult mouse hearts results in a reduced cardiac function, due to extensive loss of cardiomyocytes and formation of scar tissue by activated fibroblasts. In contrast, the newborn postnatal day 1 (P1) mouse heart is able to regenerate and restore its cardiac function following injury. However, this regenerative ability dramatically declines after P7. The molecular properties and mechanisms that facilitate neonatal heart regeneration remain unknown. To gain further insight into the realm of cardiac regeneration, our lab performed transcriptome analysis by bulk and single cell RNA-seq on P1 and P8 hearts at various time points following MI surgery. We also performed enhancer profiling by H3K27ac ChIP-seq. Coupling of both these approaches has uncovered two different gene sets that that may promote the regenerative ability of neonatal hearts: developmental genes and injury-induced genes. Amongst the neonatal-specific developmental genes, Igf2bp3, a RNA-binding protein, and Hic2, a transcriptional regulator, have been shown to promote neonatal rat ventricular cardiomyocyte (NRVM) proliferation and are currently being characterized for their involvement in neonatal heart regeneration by using gain-of-function and loss-of-function in vivo approaches. Amongst the injury-induced genes, we identified mitogens secreted from macrophages that promote NRVM proliferation. This is in line with the differential immune response elicited by P1 hearts upon MI-injury. We have also shown that an epicardial secreted factor in P1 hearts can enhance human umbilical vein endothelial cell tube formation, indicative of its role in angiogenesis. In summary, by using a multi-layered genomic analysis, we identified various genes that are involved in different cellular responses during neonatal heart regeneration. This comprehensive analysis of the neonatal regenerative response provides insights into the molecular basis of neonatal heart regeneration, and can potentially identify genes that can be modulated to facilitate adult heart regeneration.