Transforming growth factor-β1 regulates the nascent hematopoietic stem cell niche by promoting gluconeogenesis

被引：19
作者：
Zhang, C-Y [1 ,2 ]
Yin, H-M [1 ,2 ]
Wang, H. [1 ,2 ]
Su, D. [1 ,2 ]
Xia, Y. [1 ,2 ]
Yan, L-F [1 ,2 ]
Fang, B. [1 ,2 ]
Liu, W. [1 ,2 ]
Wang, Y-M [1 ,2 ]
Gu, A-H [3 ]
Zhou, Y. [1 ,2 ]
机构：
[1] Chinese Acad Sci, Univ Chinese Acad Sci, Shanghai Inst Biol Sci, Key Lab Stem Cell Biol,Inst Hlth Sci, Shanghai, Peoples R China
[2] Shanghai Jiao Tong Univ, Sch Med, Room 1618,Bldg A,320 Yue Yang Rd, Shanghai 200031, Peoples R China
[3] Nanjing Med Univ, Inst Toxicol, Sch Publ Hlth, State Key Lab Reprod Med, Nanjing 211166, Jiangsu, Peoples R China
来源：
LEUKEMIA | 2018年 / 32卷 / 02期
基金：
中国国家自然科学基金;
关键词：
GROWTH-FACTOR-BETA; FOXO TRANSCRIPTION FACTORS; LEUKEMIA-INITIATING CELLS; BONE-MARROW NICHE; TGF-BETA; TARGETED DISRUPTION; AORTIC ENDOTHELIUM; IN-VIVO; HEMOGENIC ENDOTHELIUM; METABOLIC-REGULATION;
D O I：
10.1038/leu.2017.198
中图分类号：
R73 [肿瘤学];
学科分类号：
100214 ;
摘要：
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-beta 1 in the metabolic niche of HSC emergence using the tgf-beta 1b(-/-) zebrafish. Our findings first showed that Tgf-beta 1 transcripts were enriched in the nascent HSCs. Loss of tgf-beta 1b caused a decrease of nascent HSCs within the aorta-gonad-mesonephros. Moreover, tgf-beta 1b(+) cells were runx1(+) HSCs and underwent an endothelial-to-hematopoietic-transition process. Although the autocrine of Tgf-beta 1 in HSCs rather than endothelial cells was highly demanded to regulate HSC generation, we found that tgf-beta 1b promoted HSC emergence through the endothelial c-Jun N-terminal kinase/c-Jun signaling. Chromatin immunoprecipitation (ChIP)-sequencing data showed that tgf-beta 1b/c-Jun targeted g6pc3 of FoxO signaling to promote gluconeogenesis and maintain a high glucose level in the niche. Furthermore, loss of tgf-beta 1b increased the endoplasmic-reticulum stress and oxidative stress by disturbing metabolic homeostasis. Adding a low dose of TGF-beta 1 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-beta 1 in the regulation of glucose metabolism and nascent HSC niche, which may contribute to therapies of hematological malignancies.
引用
收藏
页码：479 / 491
页数：13
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