Transcriptomic analysis of mammalian heart regeneration

GA Quaife-Ryan1, ZB Ma1, M Ramialison2, JE Hudson1 and ER Porrello1

  1. School of Biomedical Sciences, The University of Queensland, St Lucia, QLD 4072, Australia
  2. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC 3800, Australia

In comparison with the adult mammalian heart, recent evidence suggests that neonatal mice are able to regenerate following myocardial infarction (MI). Cardiac regeneration in neonatal mice is associated with induction of cardiomyocyte proliferation, which is required for faithful regeneration of the heart following injury. Recent studies also suggest that angiogenesis, immune cell infiltration and fibrotic scar regression, which are processes mediated by non-cardiomyocyte cells, are also important hallmarks of endogenous heart regeneration. However, the transcriptional programs that govern cardiomyocyte and non-myocyte behaviours during regeneration are poorly understood and gene network analyses with a multi-cellular scope are required. Here, we perform the first comprehensive analysis of cellular transcriptomes during heart development and regeneration. RNA-sequencing data were derived from 4 major cell types within the heart (cardiomyocytes, fibroblasts, endothelial cells and leukocytes) before and after myocardial infarction in neonatal (P1) and adult (P56) mice. This study reveals exquisitely controlled cell-specific transcriptional networks governing heart development and regeneration. Our findings reveal that fibroblasts and leukocytes revert to a neonatal state following MI, whereas cardiomyocytes and endothelial cells do not. By dissociating developmental and injury-induced transcriptional signatures we have also uncovered unique cellular behaviours following neonatal and adult MI. For example, the vast majority of injury-induced transcriptional changes following neonatal MI occur in the leukocyte population, whereas the majority of transcriptional changes in cardiomyocytes, fibroblasts and endothelial cells occur during development. These findings suggest that neonatal cardiomyocytes do not deploy a specific regenerative gene program following MI because they are already in a regenerative state.