Heart regeneration: staying young at heart

Associate Professor Enzo R Porrello, Murdoch Childrens Research Institute, The Royal Children’s Hospital, Parkville, VIC, Department of Physiology, The University of Melbourne, Parkville, VIC and School of Biomedical Sciences, The University of Queensland, St Lucia, QLD

The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern cardiac regenerative capacity in the neonate remains a central goal in regenerative biology. Here, we construct a transcriptional atlas of multiple cardiac cell populations in the neonatal and adult heart, which enables comparative analyses of the response to myocardial infarction for the first time. Our transcriptomic analyses identify a neonatal proliferative network, which is silenced in adult cardiomyocytes and associated with chromatin compaction around cell cycle genes during post-natal maturation. Complimentary high-throughput screening studies in human cardiac organoids revealed that a switch in metabolism from glycolysis to fatty acid oxidation drives post-natal cardiomyocyte cell cycle arrest via repression of b-catenin and Yap-dependent signaling. In ongoing studies, we are employing a number of gene therapy strategies to re-activate the neonatal proliferative network for heart regeneration. These findings uncover key transcriptional circuits underpinning the neonatal regenerative state, which could be harnessed for cardiac regeneration following injury.

Associate Professor Porrello received his PhD in Physiology from The University of Melbourne in 2009. He was subsequently awarded an NHMRC/NHF C.J. Martin fellowship to undertake postdoctoral training at UT Southwestern Medical Center in Dallas, USA, in the laboratory of Professor Eric Olson. Associate Professor Porrello returned to Australia in 2012 to establish the Cardiac Regeneration Laboratory in the School of Biomedical Sciences at The University of Queensland. He was subsequently recruited to the Murdoch Childrens Research Institute and The University of Melbourne where he will head the Cardiac Regeneration Laboratory from mid-2017. Associate Professor Porrello currently holds a joint NHMRC Career Development Fellowship and Heart Foundation Future Leader Fellowship. His research focuses on understanding the transcriptional mechanisms that control cardiac regenerative capacity during neonatal life. Associate Professor Porrello’s research has been recognized by a number of awards including the NHF Paul Korner Innovation Award, Heart Foundation Researcher of the Year, UQ Foundation for Research Excellence Award, A.K. McIntyre Prize (Australian Physiological Society) and the UT Southwestern Postdoctoral Achievement Award.