Non-Cardiomyocytes in Heart Regeneration

Heart failure represents a challenging clinical and public health problem and is associated with significant morbidity and mortality. Mechanistically, loss of cardiomyocytes leads to decompensated ventricular remodeling, which eventually progresses to cardiac failure. Regenerative medicine aimed to supplement functional cardiomyocytes is supposedly a promising approach for the effective treatment of heart failure. Over the past decades, investigations on heart regeneration have revealed the regulating networks of cardiomyocyte proliferation. Recently, the research effort has been directed to non-cardiomyocytes for heart regeneration, including cardiac fibroblasts, epicardial cells, endothelial cells, stem/progenitor cells, and immune cells. Cardiac fibroblasts not only substantially influence the composition of extracellular matrix deposition which is vital for the function and proliferation of cardiomyocytes, but also directly convert into cardiomyocytes. The epicardium is functionally important since it is involved in the cardiac development and regeneration via epicardial-mesenchymal transformation. Moreover, several immune cell lineages are found to be interspersed in heart tissue. Immune cell infiltration in combination with inflammatory reaction is found to stimulate the regenerative response in neonatal mouse heart after injury. In this review, we presented and discussed recent development in the studies on non-cardiomyocytes that directly regulate cardiomyocyte proliferation and differentiation during postnatal cardiac regeneration, with an attempt to provide information on the potential targets for the treatment of heart failure.