title: Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production.
abstract: Vitamin D insufficiency is a worldwide epidemic affecting billions of individuals, including pregnant women and children. Despite its high incidence, the impact of active vitamin D3 (1,25(OH)D3) on embryonic development beyond osteo-regulation remains largely undefined. Here, we demonstrate that 1,25(OH)D3 availability modulates zebrafish hematopoietic stem and progenitor cell (HSPC) production. Loss of Cyp27b1-mediated biosynthesis or vitamin D receptor (VDR) function by gene knockdown resulted in significantly reduced runx1 expression and Flk1+cMyb+HSPC numbers. Selective modulation in vivo and in vitro in zebrafish indicated that vitamin D3 acts directly on HSPCs, independent of calcium regulation, to increase proliferation. Notably, ex vivo treatment of human HSPCs with 1,25(OH)D3 also enhanced hematopoietic colony numbers, illustrating conservation across species. Finally, gene expression and epistasis analysis indicated that CXCL8(IL-8) was a functional target of vitamin D3-mediated HSPC regulation. Together, these findings highlight the relevance of developmental 1,25(OH)D3 availability for definitive hematopoiesis and suggest potential therapeutic utility in HSPC expansion.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Stachura
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Kwan
authors.affiliation: Department of Biological Sciences, California State University, Chico, Chico, CA 95929, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Wright
authors.affiliation: Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Linda T
authors.initials: LT
authors.lastname: Vo
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Lindsay N
authors.initials: LN
authors.lastname: Theodore
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Esain
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Isaura M
authors.initials: IM
authors.lastname: Frost
authors.affiliation: Boston Children's Hospital, Boston, MA 02115, USA.
authors.forename: Thorsten M
authors.initials: TM
authors.lastname: Schlaeger
authors.affiliation: Brigham and Women's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Boston Children's Hospital, Boston, MA 02115, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA; Harvard Stem Cell Institute, Cambridge, MA 02138, USA. Electronic address: tnorth@bidmc.harvard.edu.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
mesh_terms: D000818:Animals; D001682:Biological Availability; D020013:Calcium Signaling / Q000235:genetics; D050676:Core Binding Factor Alpha 2 Subunit / Q000235:genetics; D003577:Cytochrome P-450 Enzyme System / Q000235:genetics*; D047108:Embryonic Development / Q000235:genetics; D005260:Female; D018507:Gene Expression Regulation, Developmental; D006410:Hematopoiesis / Q000235:genetics; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics* / Q000378:metabolism; D011247:Pregnancy; D018167:Receptors, Calcitriol / Q000235:genetics*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000235:genetics; D014807:Vitamin D / Q000235:genetics* / Q000378:metabolism; D014808:Vitamin D Deficiency / Q000235:genetics / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development; D029961:Zebrafish Proteins / Q000235:genetics*
chemical_list: D050676:Core Binding Factor Alpha 2 Subunit; D016209:Interleukin-8; D018167:Receptors, Calcitriol; D029961:Zebrafish Proteins; C472526:runx1 protein, zebrafish; D014807:Vitamin D; D003577:Cytochrome P-450 Enzyme System; C000610581:Cyp27c1 protein, zebrafish; D040301:Vascular Endothelial Growth Factor Receptor-2
keywords: 1,25(OH)D3; CFU-C; cxcl8; hUCB; hematopoietic stem cell (HSC); vitamin D; zebrafish