Vitamin D Stimulates Cardiomyocyte Proliferation and Controls Organ Size and Regeneration in Zebrafish

Attaining proper organ size during development and regeneration hinges on the activity of mitogenic factors. Here, we performed a large-scale chemical screen in embryonic zebrafish to identify cardiomyocyte mitogens. Although commonly considered anti-proliferative, vitamin D analogs like alfacalcidol had rapid, potent mitogenic effects on embryonic and adult cardiomyocytes in vivo. Moreover, pharmacologic or genetic manipulation of vitamin D signaling controlled proliferation in multiple adult cell types and dictated growth rates in embryonic and juvenile zebrafish. Tissue-specific modulation of vitamin D receptor (VDR) signaling had organ-restricted effects, with cardiac VDR activation causing cardiomegaly. Alfacalcidol enhanced the regenerative response of injured zebrafish hearts, whereas VDR blockade inhibited regeneration. Alfacalcidol activated cardiac expression of genes associated with ErbB2 signaling, while ErbB2 inhibition blunted its effects on cell proliferation. Our findings identify vitamin D as mitogenic for cardiomyocytes and other cell types in zebrafish and indicate a mechanism to regulate organ size and regeneration. [Display omitted] •Vitamin D activates cardiomyocyte proliferation in several contexts in zebrafish•Vitamin D controls growth rate and cycling in a wide range of adult cells•Tissue-specific modulation of vitamin D activity controls cardiac size•ErbB2 inhibition blunts vitamin D-induced cell proliferation By chemical screening, Han et al. find that vitamin D promotes cardiomyocyte proliferation during tissue growth, homeostasis, and injury-induced regeneration in zebrafish. Intact ErbB2 signaling is required for vitamin D’s effects. In addition, vitamin D has broad and potent mitogenic effects on a variety of cell types across different tissues.