Transforming growth factor-beta 1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis
Transforming growth factor-beta 1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis
复制标题
转化生长因子-β 1 通过促进糖异生来调节新生造血干细胞生态位
作者：
Zhang C-Y;Yin H-M;Wang H.;Su D.;Xia Y.;Yan L-F;Fang B.;Liu W.;Wang Y-M;Gu A-H;Zhou Y.
了解造血干细胞（HSC）的出现对于从多能前体产生HSC是重要的。然而，调控新生HSC生态位的整合信号网络仍不清楚。在此，我们利用tgf-β1b−/−斑马鱼发现了TGF-β1在HSC出现的代谢生态位中的新作用。我们的研究结果首次表明TGF-β1转录本在新生的HSC中富集。TGF-β1b的缺失可导致垂体-性腺-中肾内新生HSC的减少。此外，tgf-β1b+细胞是runx 1 + HSC，并经历了内皮细胞向造血细胞转化的过程。尽管HSC的生成需要TGF-β1的自分泌而不是内皮细胞，但我们发现TGF-β1b通过内皮细胞c-Jun N-末端激酶/c-Jun信号通路促进HSC的出现。染色质免疫沉淀（ChIP）测序结果显示，TGF-β1b/c-Jun靶向FoxO信号通路中的g6 pc 3，从而促进细胞分化，维持细胞内较高的葡萄糖水平。此外，tgf-β1b的缺失通过干扰代谢稳态而增加内质网应激和氧化应激。低剂量TGF-β1蛋白可促进小鼠胚胎干细胞向HSC分化。总之，我们的研究为TGF-β1在调节糖代谢和新生HSC生态位方面提供了新的见解，这可能有助于血液系统恶性肿瘤的治疗。
The understanding of hematopoietic stem cell (HSC) emergence is important to generate HSCs from pluripotent precursors. However, integrated signaling network that regulates the niche of nascent HSCs remains unclear. Herein, we uncovered a novel role of TGF-β1 in the metabolic niche of HSC emergence using the tgf-β1b−/− zebrafish. Our findings first showed that Tgf-β1 transcripts were enriched in the nascent HSCs. Loss of tgf-β1b caused a decrease of nascent HSCs within the aorta-gonad-mesonephros. Moreover, tgf-β1b+ cells were runx1+ HSCs and underwent an endothelial-to-hematopoietic-transition process. Although the autocrine of Tgf-β1 in HSCs rather than endothelial cells was highly demanded to regulate HSC generation, we found that tgf-β1b promoted HSC emergence through the endothelial c-Jun N-terminal kinase/c-Jun signaling. Chromatin immunoprecipitation (ChIP)-sequencing data showed that tgf-β1b/c-Jun targeted g6pc3 of FoxO signaling to promote gluconeogenesis and maintain a high glucose level in the niche. Furthermore, loss of tgf-β1b increased the endoplasmic-reticulum stress and oxidative stress by disturbing metabolic homeostasis. Adding a low dose of TGF-β1 protein could promote the differentiation of mouse embryonic stem cells towards HSCs in vitro. Altogether, our study provided insights into a new feature of TGF-β1 in the regulation of glucose metabolism and nascent HSC niche, which may contribute to therapies of hematological malignancies.