Functionally conserved non-coding regulators of cardiomyocyte proliferation and regeneration in mouse and human

Coronary heart disease is amongst the commonest causes of death worldwide. Following myocardial infarction (MI), damaged myocardium in adult mammals is replaced by scar tissue triggering cardiac remodelling and dysfunction. Whilst teleost fish and some amphibians can, throughout their lifespan, regrow large portions of their limbs and internal organs following injury or excision, including the heart, mammals have limited regenerative ability. Neonatal mice can regenerate their hearts in the first days of their life, though not in later life, but the precise mechanisms are unclear. To investigate the regulators of mammalian heart regeneration we performed an in-depth analysis of the coding and non-coding mouse left ventricle transcriptome at key time points in early postnatal mouse heart development and during the period of regeneration following neonatal MI. These data defined the major sets of differentially expressed RNAs during normal postnatal cardiac development and following post-neonatal MI. We then demonstrated the regulatory role for key subsets of these miRNAs in cardiomyocyte proliferation and mitosis, both in mouse cardiomyocytes and in human induced pluripotent stem cell-derived cardiomyocytes. The sets of mRNAs, miRNAs and lncRNAs that we report merit further investigation as gatekeepers of cell division in the postnatal heart, providing new insights into the functions of non-coding RNAs and a valuable resource for further experimentation in regenerative medicine. The in vivo manipulation of these RNAs could potentially lead to extension of the period of mammalian cardiac regeneration beyond the neonatal period.