Stimulating Cardiogenesis as a Treatment for Heart Failure

Abstract

After myocardial injury, cardiomyocyte loss cannot be corrected by using currently available clinical treatments. In recent years, considerable effort has been made to develop cell-based cardiac repair therapies aimed at correcting for this loss. An exciting crop of recent studies reveals that inducing endogenous repair and proliferation of cardiomyocytes may be a viable option for regenerating injured myocardium. Here, we review current heart failure treatments, the state of cardiomyocyte renewal in mammals, and the molecular signals that stimulate cardiomyocyte proliferation. These signals include growth factors, intrinsic signaling pathways, microRNAs, and cell cycle regulators. Animal model cardiac regeneration studies reveal that modulation of exogenous and cell-intrinsic signaling pathways can induce reentry of adult cardiomyocytes into the cell cycle. Using direct myocardial injection, epicardial patch delivery, or systemic administration of growth molecules, these studies show that inducing endogenous cardiomyocytes to self-renew is an exciting and promising therapeutic strategy to treat cardiac injury in humans.

Keywords: adult; heart failure; myocardium; ploidy; regeneration.

Figure 1:. Renewal rates of human cardiomyocytes.

A) Timeline and rate calculated retrospectively using mathematical modeling and carbon dating measurements. B) Current theories describing the source of new ¹⁴C during aging: Left-labeled non-cardiomyoctyes fuse with cardiomyoctyes, leading to false-positive labeling. Middle-increased ploidy of cardiomyoctyes without cell division, Right-bona fide cardiomyoctye renewal. (Illustration Credit: Ben Smith).

Figure 2:. Molecular signals that stimulate cardiac repair.

Exogenous signaling by growth factors, such as NRG/ERBB and IGF family members, activates intracellular pathways that promote cardiomyocyte (CM) proliferation and regeneration mechanisms. The Hippo kinase pathway is an intrinsic signaling pathway that triggers inhibitory phosphorylation of the CM proliferation protein Yap. This leads to either Yap sequestration at the plasma membrane with the dystrophin glycoprotein complex (DGC) or in the cytosol with 14–3-3 (dashed arrows). Treatment of CMs with agrin or anti-Hippo (shSalv) molecules promotes localization of dephosphorylated Yap to the nucleus to drive expression of CM renewal genes. MicroRNAs (miRs) can positively or negatively regulate CM proliferation, and development of anti-miR antagomiR molecules have innovated cardiac repair strategies. The CM cell cycle can be reactivated via modulation of regulators such as Cyclin A2 and member of the Cyclin B and Cyclin D families. Delivery of Wee1 and TGFb inihibitor molecules enhances cyclin/CDK-induced cardiac repair. CM proliferation: positive regulators (green), negative regulators (red). . (Illustration Credit: Ben Smith).