Cardiac regeneration strategies: Staying young at heart

Abstract

The human heart is continually operating as a muscular pump, contracting, on average, 80 times per minute to propel 8000 liters of blood through body tissues each day. Whereas damaged skeletal muscle has a profound capacity to regenerate, heart muscle, at least in mammals, has poor regenerative potential. This deficiency is attributable to the lack of resident cardiac stem cells, combined with roadblocks that limit adult cardiomyocytes from entering the cell cycle and completing division. Insights for regeneration have recently emerged from studies of animals with an elevated innate capacity for regeneration, the innovation of stem cell and reprogramming technologies, and a clearer understanding of the cardiomyocyte genetic program and key extrinsic signals. Methods to augment heart regeneration now have potential to counteract the high morbidity and mortality of cardiovascular disease.

Figure 1. Implanting stem cell-derived cardiomyocytes for regeneration

ESC- or iPSC-derived cardiomyocytes are produced and expanded in vitro for delivery into the injured heart. Synthetic or natural scaffolds can assist engraftment of transplanted cardiomyocytes or used to stimulate endogenous repair mechanisms when transplanted alone.

Figure 2. Direct reprogramming: from scar to muscle

Methodology for direct cardiac programming uses combinations of known factors or small molecules to reprogram fibroblasts into cardiomyocyte-like cells. For genes or compounds to be effective in vivo, the appropriate vectors, factors, and drugs must be injected directly into the infarct in attempts to reprogram resident cardiac fibroblasts.

Figure 3. Current models for heart regeneration

(Top) Adult zebrafish regenerate cardiac muscle lost from resection of the ventricular apex (shown) or other injuries through cardiomyocyte proliferation. (Middle) Neonatal mice possess a regenerative response to cardiac injury (an MI model is shown including a suture), with compensatory proliferation that minimizes effects of the injury during a period of cardiac growth. (Bottom) Adult mice show minimal hyperplasia in response to an MI injury, which instead results in scarring.

Figure 4. Pathways to regeneration by cardiomyocyte proliferation

Pathways that promote division of cardiomyocytes can be targets for improving heart regeneration. Recent studies indicate that modulation of NRG1-ERBB signaling, Hippo-YAP signaling, hypoxia and reactive oxygen species, or influences on the dystrophin glycoprotein complex (DGC) and/or sarcomere organization can alter the limited proliferative response of cardiomyocytes (CM) in vivo. (Call out each feature here or in the text above or eliminate that detail. Now done)