Abstract 19099: Epicarial Progenitors Contribute to Neonatal Mammalian Heart Regeneration

Abstract

Heart failure is a costly and deadly disease affecting over 5 million Americans. At the core of the pathophysiology of heart failure is the inability of the adult mammalian heart to regenerate following injury. In sharp contrast to the adult mammalian heart, we recently showed that the neonatal mammalian heart is capable of complete regeneration, including re-vascularization of the myocardium, following resection of the ventricular apex or myocardial infarction (MI). However, this remarkable regenerative capacity is lost by 7 days post natally. The regenerative response of the neonatal mouse heart is mediated mostly by proliferation of pre-existing cardiomyocytes, which is in line with the mechanism of zebrafish heart regeneration. We also have shown that neonatal heart injury is associated with epicardial activation, which is also a hallmark of zebrafish heart regeneration. However, the lineage contribution of epicardial cells during neonatal mouse heart regeneration remains to be determined. We performed genetic lineage tracing data using Capsulin (Cap)MerCreMer knock-in mouse crossed with Rosa26/tdTomato reporter mouse, in which epicardial cells are specifically and irreversibly labeled by tamoxifen pulse at postnatal day 0, revealed the contribution of neonatal epicardium to multiple lineages of the heart, including the majority of interstitial fibroblasts, vascular endothelial and smooth muscle cells both during normal post natal growth and after injury.. Considering that embryonic epicardial cells contribute to fibroblasts, vascular endothelial/smooth muscle cells and in contrast adult epicardium only contribute to interstitial fibroblasts and very rarely to vascular smooth muscle cells after the injury, it appears that lineage contribution of epicardial cells is highly correlated with the capacity for neovascularization following cardiac injury. These findings uncover a novel and important role of Capsulin positive epicardium derived cells in vasculogenesis during neonatal heart development and regeneration, and opens the door for future studies to better understand the dynamics of Capsulin expression and function in the post-natal mammalian heart.