Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation

Stem Cell Reports. 2015 Oct 13;5(4):471-9. doi: 10.1016/j.stemcr.2015.08.010. Epub 2015 Sep 10.

Abstract

Hematopoietic stem and progenitor cells (HSPCs) are born from hemogenic endothelium in the dorsal aorta. Specification of this hematopoietic niche is regulated by a signaling axis using Hedgehog (Hh) and Notch, which culminates in expression of Runx1 in the ventral wall of the artery. Here, we demonstrate that the vitamin D precursor cholecalciferol (D3) modulates HSPC production by impairing hemogenic vascular niche formation. Accumulation of D3 through exogenous treatment or inhibition of Cyp2r1, the enzyme required for D3 25-hydroxylation, results in Hh pathway antagonism marked by loss of Gli-reporter activation, defects in vascular niche identity, and reduced HSPCs. Mechanistic studies indicated the effect was specific to D3, and not active 1,25-dihydroxy vitamin D3, acting on the extracellular sterol-binding domain of Smoothened. These findings highlight a direct impact of inefficient vitamin D synthesis on cell fate commitment and maturation in Hh-regulated tissues, which may have implications beyond hemogenic endothelium specification.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cholecalciferol / metabolism
  • Cholecalciferol / pharmacology*
  • Cholestanetriol 26-Monooxygenase / genetics
  • Cholestanetriol 26-Monooxygenase / metabolism
  • Gene Deletion
  • Hedgehog Proteins / metabolism*
  • Hematopoiesis / drug effects*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / drug effects*
  • Receptors, G-Protein-Coupled / metabolism
  • Signal Transduction / drug effects
  • Smoothened Receptor
  • Vitamins / metabolism
  • Vitamins / pharmacology*
  • Zebrafish / embryology*
  • Zebrafish / genetics
  • Zebrafish / metabolism
  • Zebrafish Proteins / genetics
  • Zebrafish Proteins / metabolism*

Substances

  • Hedgehog Proteins
  • Receptors, G-Protein-Coupled
  • Smoothened Receptor
  • Vitamins
  • Zebrafish Proteins
  • smo protein, zebrafish
  • Cholecalciferol
  • Cholestanetriol 26-Monooxygenase