However, there is little evidence that the transplanted cells are retained in injured hearts, and the mechanistic basis of cardiac improvement following stem cell delivery remains unclear. Studies in animal models and humans have demonstrated that cellular replacement strategies for heart repair, in which stem cells and other cell types are injected directly into the injured heart or into the coronary circulation, can have modest beneficial effects on cardiac function 7, 8. Over the past decade, considerable effort and resources have gone into the development of stem cell-based therapies for cardiac repair 3– 6. This underscores the need for innovative strategies for heart repair. The adult mammalian heart cannot efficiently generate new cardiac muscle cells in response to injury, and although numerous drugs and mechanical devices can temporarily improve cardiac function, such approaches do not replace lost cardiac muscle and are inevitably transient.
Numerous insults, including ischaemic coronary artery disease, hypertension, genetic mutations and chemotherapy, can cause heart disease, which is associated with loss or dysfunction of cardiac muscle cells, diminished pump function, arrhythmias and eventual death 2. Thus, it is not surprising that congenital and acquired diseases of the heart can have catastrophic consequences and that heart disease is the most common cause of adult death worldwide 1. The life of all animals, from early embryogenesis and throughout adulthood, depends on the second to second uninterrupted function of the heart. Recent advances in understanding the mechanistic basis of heart development offer exciting opportunities for effective therapies for heart failure. Stimulating cardiomyocyte dedifferentiation and proliferation by activating mitotic signalling pathways involved in embryonic heart growth represents a complementary approach for heart regeneration and repair. Heart function has been restored in rodents by reprogramming non-myocytes into cardiomyocytes, by expressing transcription factors (GATA4, HAND2, myocyte-specific enhancer factor 2C (MEF2C) and T-box 5 (TBX5)) and microRNAs (miR-1, miR-133, miR-208 and miR-499) that control cardiomyocyte identity. The cellular processes and regulatory mechanisms involved in heart growth and development can be exploited to repair the injured adult heart through ‘reawakening’ pathways that are active during embryogenesis. As the adult mammalian heart has limited potential for regeneration and repair, the loss of cardiomyocytes during injury and disease can result in heart failure and death.
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