Mammalian Heart Regeneration
The Race to the Finish Line
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A long-standing goal of cardiovascular scientists is to repair damaged hearts after myocardial infarction by overcoming the limited regenerative capacity of the adult mammalian heart. Many new strategies are being actively investigated for generating functional cardiomyocytes or progenitor cells. The race is on for the first demonstration of durable therapeutic heart repair in human.
The classical paradigm that the adult mammalian heart is a postmitotic, terminally differentiated organ has been actively debated. Data from 14C dating studies have demonstrated a limited self-renewal capacity of the adult mammalian heart that declines with age.1 These repair processes are, however, insufficient to compensate for extensive cell loss occurring after acute or chronic cardiac injury. Therefore, investigators in cardiovascular regenerative medicine have actively explored different approaches to replace the postinfarct scar tissue with contractile muscle cells. Despite these efforts, a central question for the field of cardiac regenerative medicine remains: what strategy will take us to the finish line in this race to achieve complete heart regeneration? In this Viewpoint article, we comment on recent experimental and clinical approaches to regenerate the failing heart and highlight the urgent need to clarify the biology of cardiomyocyte (CM) development, growth, and maturation.
Mechanisms of Endogenous Regeneration
The mammalian heart harbors multiple cell types that may be targeted in regenerative strategies. Conceptually, the most direct approach is to stimulate pre-existing CMs to re-enter the cell cycle. Alternatively, resident cardiomyogenic stem/progenitor cell populations have been described to differentiate directly into CMs. Although there are advantages and disadvantages to each approach, it is clear that both strategies have demonstrated early promises that require further improvement and independent validation in nonrodent models.
Induction of Cardiomyocyte Division
The regenerative capacity of the neonatal mammalian heart seems to be greater than that of adult heart because of the presence of a short window of CM proliferative competence.2 Immediately …