Activation of the vitamin D receptor transcription factor stimulates the growth of definitive erythroid progenitors
Activation of the vitamin D receptor transcription factor stimulates the growth of definitive erythroid progenitors
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DOI：
10.1182/bloodadvances.2018017533
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发表时间：
2018-06-12
期刊：
影响因子：
7.5
通讯作者：
Baron, Margaret H.
中科院分区：
文献类型：
--
作者：
Barminko, Jeffrey;Reinholt, Brad M.;Baron, Margaret H.
调节红系祖细胞生长的途径还不完全清楚。在红系个体发育过程中基因表达变化的计算分析中，维生素D受体（Vdr）核激素受体转录因子基因在胎儿和成人阶段被鉴定，但在胚胎发育阶段未被鉴定。Vdr在定形红系祖细胞（EryD）中表达，并在其成熟过程中下调。维生素D3激动剂骨化三醇激活Vdr信号增加了胎肝和成人骨髓中EryD集落的生长，维持了祖细胞的潜能，并延迟了红系成熟，如克隆形成试验、悬浮培养、细胞表面表型和基因表达分析所示。Lin（neg）cKit（+）细胞的早期（cKit（+）CD 71（lo/neg））而非晚期（cKit（+）CD 71（hi））EryD祖细胞亚群对骨化三醇有反应。在维生素D3和糖皮质激素受体配体的存在下培养cKit（+）CD 71（lo/neg）祖细胞导致增殖增加，与单独的任一配体相比至少是累加的。慢病毒shRNA介导的Vdr表达的敲低废除了骨化三醇对早期红系祖细胞生长的刺激。这些发现表明，Vdr在早期红系祖细胞中具有细胞内在功能。靶向Vdr信号通路的下游组分可能导致用于离体扩增红系祖细胞的新方法。
The pathways that regulate the growth of erythroid progenitors are incompletely understood. In a computational analysis of gene expression changes during erythroid ontogeny, the vitamin D receptor (Vdr) nuclear hormone receptor transcription factor gene was identified in fetal and adult stages, but not at the embryonic stage of development. Vdr was expressed in definitive erythroid (EryD) progenitors and was downregulated during theirmaturation. Activation of Vdr signaling by the vitamin D3 agonist calcitriol increased the outgrowth of EryD colonies from fetal liver and adult bone marrow, maintained progenitor potential, and delayed erythroid maturation, as revealed by clonogenic assays, suspension culture, cell surface phenotype, and gene expression analyses. The early (cKit(+)CD71(lo/neg)), but not the late (cKit(+)CD71(hi)), EryD progenitor subset of Lin(neg)cKit(+) cells was responsive to calcitriol. Culture of cKit(+)CD71(lo/neg) progenitors in the presence of both vitamin D3 and glucocorticoid receptor ligands resulted in an increase in proliferation that was at least additive compared with either ligand alone. Lentivirus shRNA-mediated knockdown of Vdr expression abrogated the stimulation of early erythroid progenitor growth by calcitriol. These findings suggest that Vdr has a cell-intrinsic function in early erythroid progenitors. Targeting of downstream components of the Vdr signaling pathway may lead to new approaches for the expansion of erythroid progenitors ex vivo.