Strategies for cardiac regeneration and repair

Abstract

Heart failure is a growing epidemic caused by cardiomyocyte depletion. Current therapies prolong survival by protecting remaining cardiomyocytes but are unable to overcome the fundamental problem of regenerating lost cardiomyocytes. Several strategies for promoting heart regeneration have emerged from decades of intensive study. Although some of these strategies remain confined to basic research, others are beginning to be tested in humans. We review strategies for cardiac regeneration and summarize progress of related clinical trials.

Figure 1. Cardiomyocyte loss in Myocardial Infarction

Myocardial infarction causes loss of ~1 billion cardiomyocytes in the adult heart. After the acute event, there is progressive fibrosis and myocyte loss in the infarct border zone, and remaining cardiomyocytes undergo hypertrophy. Standard therapy is designed to preserve remaining cardiomyocytes, with variable efficacy.

Figure 2. Cardiac regeneration through stimulation of adult cell cycle re-entry

Existing cardiomyocytes (blue nuclei) proliferate to replenish lost cardiomyocytes (green nuclei). Cardiomyocyte refreshment through stimulation of endogenous pathways may allow newly formed cardiomyocytes to integrate and recruit their own vasculature.

Figure 3. Cardiac regeneration through cell therapy

A. Embryonic- or iPSC-derived cardiomyocytes (green cells) are produced in vitro and delivered to myocardium, possibly with paracrine factors and engineered scaffolds that enhance engraftment and functional integration. B. Resident and non-resident cardiac progenitors (purple cells) are isolated, expanded in vitro, and delivered to myocardium. Although initially envisioned to improve myocardial outcome by engraftment and cardiogenic activity, benefit observed from cardiac progenitor therapy currently undergoing clinical trials suggests that benefit comes from paracrine activity of injected cells, which do not stably engraft in host myocardium.

Figure 4. Modulating resident cardiac progenitor activity in situ

Resident cardiac progenitors could be recruited for cardiac regeneration by treatment with paracrine factors that enhance their amplification and mobilization, and that redirect their fate decisions.

Figure 5. Refreshing cardiomyocytes by cellular reprogramming

Proliferating fibroblasts of the injured heart may be recruited to replenish cardiomyocytes by delivering reprogramming factors that induce them to transdifferentiate into cardiomyocyte-like cells (blue).