Abstract
In the past few decades, cardiac regeneration has been the central target for restoring the injured heart. In mammals, cardiomyocytes are terminally differentiated and rarely divide during adulthood. Embryonic and fetal cardiomyocytes undergo robust proliferation to form mature heart chambers in order to accommodate the increased workload of a systemic circulation. In contrast, postnatal cardiomyocytes stop dividing and initiate hypertrophic growth by increasing the size of the cardiomyocyte when exposed to increased workload. Extracellular and intracellular signaling pathways control embryonic cardiomyocyte proliferation and postnatal cardiac hypertrophy. Harnessing these pathways could be the future focus for stimulating endogenous cardiac regeneration in response to various pathological stressors. Meanwhile, patient-specific cardiomyocytes derived from autologous induced pluripotent stem cells (iPSCs) could become the major exogenous sources for replenishing the damaged myocardium. Human iPSC-derived cardiomyocytes (iPSC-CMs) are relatively immature and have the potential to increase the population of cells that advance to physiological hypertrophy in the presence of extracellular stimuli. In this review, we discuss how cardiac proliferation and maturation are regulated during embryonic development and postnatal growth, and explore how patient iPSC-CMs could serve as the future seed cells for cardiac cell replacement therapy.
Highlights
Heart failure has been a leading cause of morbidity and mortality in the world, affecting more than 40 million people
The damaged heart undergoes extensive remodeling to replenish the dead cardiomyocytes with fibrotic scars and pathological hypertrophy, which significantly impairs the Cardiomyocyte Proliferation and Maturation normal cardiac function and eventually results in the development of chronic heart failure with either preserved ejection fraction (HFpEF) or reduced ejection fraction (HFrEF) (Swynghedauw, 1999; Borlaug and Paulus, 2011)
We explore the mechanistic insights of cardiomyocyte proliferation and maturation from the perspectives of cardiac differentiation of human pluripotent stem cells (PSCs)
Summary
Heart failure has been a leading cause of morbidity and mortality in the world, affecting more than 40 million people. The blood flow decreases or stops to supply to a part of the heart, which leads to severe damage to cardiac muscle. Adult cardiomyocytes are not capable of robust proliferation to regenerate the damaged myocardium. Regenerating the damaged cardiac muscle is the key point to restore the normal cardiac function in heart failure. Therapeutic intervention strategies can be summarized into two categories: (1) stimulation of the proliferation of endogenous cardiomyocytes; and (2) transplantation of exogenous stem cells that can regenerate the damaged heart. Recent studies using human PSC-derived cardiomyocytes and cardiac patches have shown promising therapeutic treatment of myocardial infarction in large animal models, shedding light on the future cardiac regeneration therapies (Chong et al, 2014; Liu et al, 2018). We envision the future use of human iPSC-derived cardiomyocytes for treating cardiovascular disease
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