Fate of developmental mechanisms of myocardial plasticity in the postnatal heart

Abstract

SUMMARYWhether the heart’s organ-founding, progenitor cell gene regulatory networks (CPC-GRNs) are sustained after birth and can be therapeutically evoked for regeneration in response to disease, remains elusive. Here, we report a spatiotemporally resolved analysis of CPC-GRN deployment dynamics, through the pan-CPC-GRN gene Isl1. We show that the Isl1-CPC-GRNs that are deployed during early cardiogenesis and generate the cardiomyocyte majority from mesoderm, undergo programmed silencing through proteasome- and PRC2-mediated Isl1 repression, selectively in the arterial pole. In contrast, we identify a neural crest (CNC)-specific Wnt/β-catenin/Isl1-CPC-GRN that is deployed through the venous pole during cardiac growth and partitioning, and contributes a minority of cardiomyocytes which, in turn, expand massively to build ~10% of the biventricular myocardium. These “dorsal CNCs” continue to sporadically generate cardiomyocytes throughout postnatal growth which, however, are non-proliferative, suggesting that partitioning-like, fetal proliferation signals could be therapeutically targeted to evoke clonal expansion capacity in postnatal CNC-cardiomyocytes for heart regeneration.

Neuregulin-1, in a Conducive Milieu with Wnt/BMP/Retinoic Acid, Prolongs the Epicardial-Mediated Cardiac Regeneration Capacity of Neonatal Heart Explants

“…This report provides a novel and much-needed platform from which to address these important questions. Understanding the cell-intrinsic and extrinsic mechanisms governing regeneration of the neonatal murine heart can illuminate the fixed and flexible components of a cellular and molecular response to cardiac injury [64] . Such knowledge is critical to understanding the current limitations and future potential for repair in the injured adult human heart.…”