ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver

Yunze Zhao, Jie Zhou, Dan Liu, Fang Dong, Hui Cheng, Weili Wang, Yakun Pang, Yajie Wang, Xiaohuan Mu, Yanli Ni, Zhuan Li, Huiyu Xu, Sha Hao, Xiaochen Wang, Shihui Ma, Qian-fei Wang, Guozhi Xiao, Weiping Yuan, Bing Liu and Tao Cheng

Key points

  • ATF4 positively regulates expansion of functional HSCs in mouse fetal liver.

  • ATF4-Angptl3 axis in niche cells is pivotal for HSC maintenance in fetal liver.


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.

  • Submitted March 9, 2015.
  • Accepted September 8, 2015.