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

Dev Cell. 2019 Mar 25;48(6):853-863.e5. doi: 10.1016/j.devcel.2019.01.001. Epub 2019 Jan 31.


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.

Keywords: ErbB2 signaling; cardiomyocyte; cell proliferation; chemical screen; heart; mitogen; regeneration; size control; vitamin D; zebrafish.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects
  • Embryo, Nonmammalian / cytology
  • Embryo, Nonmammalian / drug effects
  • Heart / anatomy & histology*
  • Heart / drug effects
  • Heart / physiology*
  • Mitogens / pharmacology
  • Myocytes, Cardiac / cytology*
  • Myocytes, Cardiac / drug effects
  • Myocytes, Cardiac / metabolism
  • Organ Size / drug effects
  • Organ Specificity
  • Regeneration / drug effects*
  • Signal Transduction / drug effects
  • Vitamin D / pharmacology*
  • Zebrafish / anatomy & histology*
  • Zebrafish / embryology
  • Zebrafish / physiology*
  • Zebrafish Proteins / metabolism


  • Mitogens
  • Zebrafish Proteins
  • Vitamin D