Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production.
Developmental Vitamin D Availability Impacts Hematopoietic Stem Cell Production.
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DOI：
10.1016/j.celrep.2016.09.012
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发表时间：
2016-10-04
期刊：
影响因子：
8.8
通讯作者：
North TE
中科院分区：
文献类型：
--
作者：
Cortes M;Chen MJ;Stachura DL;Liu SY;Kwan W;Wright F;Vo LT;Theodore LN;Esain V;Frost IM;Schlaeger TM;Goessling W;Daley GQ;North TE
维生素 D 缺乏是一种世界范围内的流行病，影响着数十亿人，其中包括孕妇和儿童。尽管发生率很高，但活性维生素 D3 (1,25(OH)D3) 对骨调节之外的胚胎发育的影响在很大程度上仍不清楚。在这里，我们证明 1,25(OH)D3 的可用性可调节斑马鱼造血干细胞和祖细胞 (HSPC) 的产生。基因敲除导致 Cyp27b1 介导的生物合成或维生素 D 受体 (VDR) 功能丧失，导致 runx1 表达和 Flk1+cMyb+ HSPC 数量显着降低。斑马鱼体内和体外的选择性调节表明，维生素 D3 直接作用于 HSPC，不依赖于钙调节，以增加增殖。值得注意的是，用 1,25(OH)D3 对人类 HSPC 进行离体处理也增加了造血集落数量，说明了跨物种的保守性。最后，基因表达和上位分析表明 CXCL8 (IL-8) 是维生素 D3 介导的 HSPC 调节的功能靶标。总之，这些发现强调了发育中 1,25(OH)D3 可用性与确定性造血的相关性，并表明了 HSPC 扩增的潜在治疗用途。
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.