title: ATF4 plays a pivotal role in the development of functional hematopoietic stem cells in mouse fetal liver.
abstract: The fetal liver (FL) serves as a predominant site for expansion of functional hematopoietic stem cells (HSCs) during mouse embryogenesis. However, the mechanisms for HSC development in FL remain poorly understood. In this study, we demonstrate that deletion of activating transcription factor 4 (ATF4) significantly impaired hematopoietic development and reduced HSC self-renewal in FL. In contrast, generation of the first HSC population in the aorta-gonad-mesonephros 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 FL was significantly compromised in the absence of ATF4. Gene profiling using RNA-seq revealed downregulated 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, chromatin immunoprecipitation assay in conjunction with silencing RNA-mediated silencing and complementary DNA overexpression showed transcriptional control of Angptl3 by ATF4. To summarize, ATF4 plays a pivotal role in functional expansion and repopulating efficiency of HSCs in developing FL, and it acts through upregulating transcription of cytokines such as Angptl3 in the microenvironment.
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Yunze
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Translational Medicine Center of Stem Cells, Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China;
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China;
authors.forename: Dan
authors.initials: D
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Fang
authors.initials: F
authors.lastname: Dong
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Hui
authors.initials: H
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Weili
authors.initials: W
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Yakun
authors.initials: Y
authors.lastname: Pang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Yajie
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Mu
authors.affiliation: Translational Medicine Center of Stem Cells, Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China;
authors.forename: Yanli
authors.initials: Y
authors.lastname: Ni
authors.affiliation: Translational Medicine Center of Stem Cells, Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China;
authors.forename: Zhuan
authors.initials: Z
authors.lastname: Li
authors.affiliation: Translational Medicine Center of Stem Cells, Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China;
authors.forename: Huiyu
authors.initials: H
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Sha
authors.initials: S
authors.lastname: Hao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Xiaochen
authors.initials: X
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Shihui
authors.initials: S
authors.lastname: Ma
authors.affiliation: Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing, China;
authors.forename: Qian-fei
authors.initials: QF
authors.lastname: Wang
authors.affiliation: Department of Biology and Shenzhen Key Laboratory of Cell Microenvironment, South University of Science and Technology of China, Shenzhen, China; and.
authors.forename: Guozhi
authors.initials: G
authors.lastname: Xiao
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China;
authors.forename: Weiping
authors.initials: W
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Translational Medicine Center of Stem Cells, Translational Medicine Center, Laboratory of Oncology, Affiliated Hospital of the Academy of Military Medical Sciences, Beijing, China;
authors.forename: Bing
authors.initials: B
authors.lastname: Liu
authors.affiliation: State Key Laboratory of Experimental Hematology, Institute of Hematology and Blood Disease Hospital, Center for Stem Cell Medicine, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China; Collaborative Innovation Center for Cancer Medicine, Tianjin, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Cheng
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D005333:Fetus / Q000166:cytology / Q000196:embryology*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D008099:Liver / Q000166:cytology / Q000196:embryology*; D051379:Mice; D018345:Mice, Knockout; D055153:Stem Cell Niche / Q000502:physiology*; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
chemical_list: D000091303:Angiopoietin-Like Protein 3; D000075802:Angiopoietin-like Proteins; D042682:Angiopoietins; C404495:Angptl3 protein, mouse; C081452:Atf4 protein, mouse; D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse; D051701:Activating Transcription Factor 4