Decoding developmental signaling for heart regeneration.

The adult heart consists of a fixed number of cardiomyocytes (CMs) determined at birth. CMs once lost due to injury in the adult heart are never replaced, initiating a viscous cycle of adverse events leading to heart failure. Therapeutic interventions that drive cardiac repair by proliferation of the endogenous CMs or adoptive transfer of stem cells such as cardiac tissue derived stem/progenitor cells (CPCs) are promising albeit limited in their ability to repair the heart. Numerous studies have identified an inherent regenerative power of the heart during embryonic and postnatal development. The developmental cardiac tissue can initiate a robust regenerative response leading to complete resolution of injury. Unique cellular and molecular mechanisms in the developmental heart are at the core of this regenerative ability. Upon cardiac maturation, cellular differentiation and changes in molecular signaling hubs active developmentally are 'switched off' in the adult heart. Recent work has shown convincing results for promoting cardiac repair in the adult heart by reactivation of developmental signaling. CPCs engineering with developmental factors or their CMs specific delivery of can reactivate regenerative signaling to augment cardiac structure and function in the adult heart. This review aims to summarize efforts regarding reactivation of developmental signaling factors in the heart using CPCs and CMs. A special emphasis is on embryonic/developmental microRNAs governed signaling pathways for cardiac repair. We provide an in-depth analysis of the current state of the field including discussion of some of the limitations that will be beneficial for future studies. Significance statement: Reactivation of developmental signaling in the heart is promising approach to increase cardiac regeneration after myocardial injury. This article summarizes current state of the field regarding signaling factors that regulated developmental signaling in the context of cardiac progenitor cells and cardiomyocytes to promote cell proliferation and increase their overall repair ability.