Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production

Abstract

SUMMARY 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.

Vitamin D deficiency and outcomes in pediatric hematopoietic stem cell transplantation

“…However, in a recent publication, it was reported that active vitamin D3 is both necessary and sufficient to modify embryonic hematopoietic stem cell production. This effect is due to vitamin D receptor‐mediated transcriptional activation of the inflammatory chemokine CXCL8, stimulating cell‐autonomous regulation of hematopoietic stem cell expansion and viability via CXCR1/2 activity …”

Up-Regulation of the Vitamin D Pathway in Acute Myeloid Leukemia: A Novel Cause of Hypercalcemia

“…In this study, zebrafish morpholino knockdown of essential vitamin D regulatory genes (vdra and cyp27b1) was used to show that calcitriol could modify zebrafish hematopoietic stem progenitor cell production. In addition, exposing human CD34 + umbilical cord HSCs to calcitriol ex-vivo was shown to enhance proliferation, colony forming activity and cell survival [9]. Considering these findings, it is plausible that the patient's leukemic clone co-opted the vitamin D pathway to enhance leukemic cell proliferation without impacting on differentiation.…”

“…In the aforementioned context, it is not obviously clear why up-regulation of the vitamin D pathway would be advantageous to this patient's leukemic blasts. However, a recent publication intriguingly links vitamin D metabolism to teleost developmental hematopoiesis and human umbilical cord HSC proliferation [9]. In this study, zebrafish morpholino knockdown of essential vitamin D regulatory genes (vdra and cyp27b1) was used to show that calcitriol could modify zebrafish hematopoietic stem progenitor cell production.…”

Metadichol® and CD34 Expression in Umbilical Cord Cells

“…Cortes et al [25] have pointed out how vitamin D signaling plays a role in HSPC expansion and survival in zebrafish embryos and human umbilical cord blood. They showed that HSPCs respond directly to [1,25] (OH)D3 stimulation via vitamin D receptor-induced transcriptional activation of the inflammatory cytokine CXCL8. VDR is expressed on human CD34 hematopoietic progenitors [26].…”