Blood First Edition Paper, prepublished online September 17, 2015; DOI 10.1182/blood-2015-03-633354

user-5d54d98b530c705f51c2fe5a(2015)

引用 0|浏览15
暂无评分
摘要
The fetal liver serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in fetal liver remain poorly understood. In this study, we demonstrate that deletion of the activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in fetal liver. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros (AGM) region was not affected. The migration activity of ATF4-/- HSCs was moderately reduced. Interestingly, the HSC-supporting ability of both endothelial and stromal cells in fetal liver was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed down-regulated expression of a panel of cytokines in ATF4-/-stromal cells, including angiopoietin-like protein 3 (Angptl3) and vascular endothelial growth factor-A (VEGFA). Addition of Angptl3, but not VEGFA, partially rescued the repopulating defect of ATF4-/- HSCs in the culture. Furthermore, ChIP assay in conjunction with siRNA-mediated silencing and cDNA over-expression showed transcriptional control of Angptl3 by ATF4. Taken together, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing fetal liver, and it acts through up-regulating transcription of cytokines such as Angptl3 in the microenvironment.
更多
查看译文
AI 理解论文
溯源树
样例
生成溯源树,研究论文发展脉络
Chat Paper
正在生成论文摘要