Abstract
Unlike its mammalian counterpart, the adult zebrafish heart is able to fully regenerate after severe injury. One of the most important events during the regeneration process is cardiomyocyte proliferation, which results in the replacement of lost myocardium. Growth factors that induce cardiomyocyte proliferation during zebrafish heart regeneration remain to be identified. Signaling pathways important for heart development might be reutilized during heart regeneration. IGF2 was recently shown to be important for cardiomyocyte proliferation and heart growth during mid-gestation heart development in mice, although its role in heart regeneration is unknown. We found that expression of igf2b was upregulated during zebrafish heart regeneration. Following resection of the ventricle apex, igf2b expression was detected in the wound, endocardium and epicardium at a time that coincides with cardiomyocyte proliferation. Transgenic zebrafish embryos expressing a dominant negative form of Igf1 receptor (dn-Igf1r) had fewer cardiomyocytes and impaired heart development, as did embryos treated with an Igf1r inhibitor. Moreover, inhibition of Igf1r signaling blocked cardiomyocyte proliferation during heart development and regeneration. We found that Igf signaling is required for a subpopulation of cardiomyocytes marked by gata4:EGFP to contribute to the regenerating area. Our findings suggest that Igf signaling is important for heart development and myocardial regeneration in zebrafish.
Highlights
Most adult cardiomyocytes in mammals are generally thought to have permanently exited the cell cycle and are unable to proliferate [1,2,3,4]
Cardiomyocyte proliferation plays a critical role in zebrafish myocardial regeneration [16,17]
Growth factors, secreted molecules and extracellular matrix molecules that are essential for adult zebrafish cardiomyocyte proliferation remain to be identified
Summary
Most adult cardiomyocytes in mammals are generally thought to have permanently exited the cell cycle and are unable to proliferate [1,2,3,4]. Zebrafish hearts regenerate by undergoing dedifferentiation and proliferation of cardiomyocytes [16,17]. During heart growth of mid-gestation mouse embryos, mitogens originating from the epicardium play essential roles in inducing cardiomyocyte proliferation in the myocardium. We determined the functions of Igf signaling in zebrafish heart regeneration. Igf signaling is required for proper cardiomyocyte number in zebrafish embryonic hearts. The number of ventricular cardiomyocytes (area encircled by dotted line) number decreased in embryos when Igf1r signaling was blocked. We further demonstrated that Igf signaling is required for cardiomyocyte proliferation during zebrafish heart development and regeneration. Our work identifies an evolutionarily conserved role of IGF signaling in heart development and an important role in cardiomyocyte proliferation during heart regeneration
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