Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production

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. [Display omitted] •Developmental 1,25(OH)D3 availability modulates definitive HSPC production•The effect of 1,25(OH)D3 on HSPCs is VDR-mediated and Ca2+-independent•Vitamin D supplementation significantly increases human UCB HSPCs in vitro•1,25(OH)D3 exposure promotes viability and proliferation via Cxcl8 (IL-8) activity Cortes et al. elucidate a role for vitamin D signaling in hematopoietic stem and progenitor (HSPC) expansion and survival. Using zebrafish embryos and human umbilical cord blood, they demonstrate that HSPCs respond directly to 1,25(OH)D3 stimulation via vitamin D receptor-induced transcriptional activation of the inflammatory cytokine CXCL8.