Cortes, MauricioLiu, Sarah Y.Kwan, WandaAlexa, KristenGoessling, WolframNorth, Trista E.2015-12-042015Cortes, Mauricio, Sarah Y. Liu, Wanda Kwan, Kristen Alexa, Wolfram Goessling, and Trista E. North. 2015. “Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation.” Stem Cell Reports 5 (4): 471-479. doi:10.1016/j.stemcr.2015.08.010. http://dx.doi.org/10.1016/j.stemcr.2015.08.010.2213-6711http://nrs.harvard.edu/urn-3:HUL.InstRepos:23845158Summary 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.en-USJournal Article2015-12-0410.1016/j.stemcr.2015.08.010