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

TitleVitamin D Stimulates Cardiomyocyte Proliferation and Controls Organ Size and Regeneration in Zebrafish.
Publication TypeJournal Article
Year of Publication2019
AuthorsHan, Y, Chen, A, Umansky, K-B, Oonk, KA, Choi, W-Y, Dickson, AL, Ou, J, Cigliola, V, Yifa, O, Cao, J, Tornini, VA, Cox, BD, Tzahor, E, Poss, KD
JournalDev Cell
Volume48
Issue6
Pagination853-863.e5
Date Published2019 03 25
ISSN1878-1551
KeywordsAnimals, Cell Cycle, Cell Proliferation, Embryo, Nonmammalian, Heart, Mitogens, Myocytes, Cardiac, Organ Size, Organ Specificity, Regeneration, Signal Transduction, Vitamin D, Zebrafish, Zebrafish Proteins
Abstract

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.

DOI10.1016/j.devcel.2019.01.001
Alternate JournalDev. Cell
PubMed ID30713073
PubMed Central IDPMC6435404
Grant ListR01 GM074057 / GM / NIGMS NIH HHS / United States
R01 HL081674 / HL / NHLBI NIH HHS / United States
R01 HL131319 / HL / NHLBI NIH HHS / United States
R01 HL136182 / HL / NHLBI NIH HHS / United States