title: Accumulation of the Vitamin D Precursor Cholecalciferol Antagonizes Hedgehog Signaling to Impair Hemogenic Endothelium Formation.
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.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Kwan
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Kristen
authors.initials: K
authors.lastname: Alexa
authors.affiliation: Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: tnorth@bidmc.harvard.edu.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
mesh_terms: D000818:Animals; D002762:Cholecalciferol / Q000378:metabolism / Q000494:pharmacology*; D053493:Cholestanetriol 26-Monooxygenase / Q000235:genetics / Q000378:metabolism; D017353:Gene Deletion; D053823:Hedgehog Proteins / Q000378:metabolism*; D006410:Hematopoiesis / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000072086:Smoothened Receptor; D014815:Vitamins / Q000378:metabolism / Q000494:pharmacology*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; D014815:Vitamins; D029961:Zebrafish Proteins; C491021:smo protein, zebrafish; D002762:Cholecalciferol; D053493:Cholestanetriol 26-Monooxygenase