HIF1α-induced PDGFRβ signaling promotes developmental HSC production via IL-6 activation.
HIF1α-induced PDGFRβ signaling promotes developmental HSC production via IL-6 activation.
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DOI：
10.1016/j.exphem.2016.10.002
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发表时间：
2017-02
影响因子：
2.6
通讯作者：
North TE
中科院分区：
文献类型：
--
作者：
Lim SE;Esain V;Kwan W;Theodore LN;Cortes M;Frost IM;Liu SY;North TE
造血干细胞(HSCs)具有自我更新和分化为所有成熟血细胞系的能力，从而重建整个血液系统。因此，造血干细胞在治疗血液系统恶性肿瘤和骨髓衰竭方面具有很高的治疗价值。我们最近发现，短暂的葡萄糖升高通过增加代谢活性和随后ROS介导的低氧诱导因子1α(HIF1α)诱导HSCs产生剂量依赖性效应。作为HIF1α靶点的血小板衍生生长因子B(PDGFb)及其受体PDGFRb在代谢刺激下显著上调。虽然PDGF信号在血管发育中的作用已得到很好的证实，但它在造血中的作用却知之甚少。通过RUNX1、cmyb Wish和HSPC-Reportβ分析确定，暴露于PAN-PDGFR抑制剂或PDGFFRα选择性拮抗剂可阻断HSPC形成中HIF1DNA的升高。吗啡抑制PDGFRb或显性阴性PDGFRb表达也有类似的结果，提示PDGFRbβ信号是HIF1α介导的HSPC诱导的关键下游介质。值得注意的是，pdgfb配体的过表达增加了36hpf的AGM和48hpf的CHT中的HSPC数量。通过定量聚合酶链式反应对已知的PDGFB/PDGFFRβ调控靶点的研究发现，炎症介质，包括白介素6(IL-6)及其受体(IL-6R)显著增加。钼介导的IL-6下调或化学抑制IL-6R可拮抗pdgfb过表达的影响；此外，IL-6/IL-6R功能的上位性分析证实了HIF1α下游的活性。综上所述，这些发现定义了HIF1α通过PBFGB/PDGFRβ和IL-6/IL-6R调节的信号轴，从而控制胚胎HSPC的产生。
Hematopoietic stem cells (HSCs) have the ability to both self-renew and differentiate into all the mature blood cell lineages and thereby reconstitute the entire blood system. As such, HSCs are therapeutically valuable for treatment of hematological malignances and bone marrow failure. We recently showed that transient glucose elevation elicited dose-dependent effects on HSCs through elevated metabolic activity and subsequent ROS-mediated induction of Hypoxia Inducible Factor 1α (Hif1α). Platelet Derived Growth Factor B (pdgfb), a Hif1α-target, and its receptor, pdgfrb, were significantly upregulated in response to metabolic stimulation. While the function of PDGF-signaling is well established in vascular development, its role in hematopoiesis is less understood. Exposure to either a pan-PDGF inhibitor or a PDGFRβ-selective antagonist in the context of Hif1α stimulation blocked elevations in HSPC formation as determined by runx1;cmyb WISH and HSPC-reporter FACS analysis. Similar results were observed for morpholino knockdown of pdgfrb or dominant negative pdgfrb expression, indicating PDGFRβ signaling is a key downstream mediator of Hif1α-mediated induction of HSPCs. Notably, overexpression of pdgfb ligand enhanced HSPC numbers in the AGM at 36hpf and in the CHT at 48hpf. A survey of known PDGF-B/PDGFRβ regulatory targets by qPCR revealed a significant increase in inflammatory intermediates, including interleukin 6 (IL-6) and its receptor (IL-6R). MO-mediated knockdown of il6 or chemical inhibition of IL-6R antagonized the effect of pdgfb overexpression; furthermore, epistatic analysis of IL-6/IL-6R function confirmed activity downstream of Hif1α. Together these findings define a Hif1α-regulated signaling axis through PBFGB/PDGFRβ and IL-6/IL-6R that acts to control embryonic HSPC production.