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

Abstract

Key Points• ATF4 positively regulates expansion of functional HSCs in mouse FL.• ATF4-Angptl3 axis in niche cells is pivotal for HSC maintenance in FL.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 2/2 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 2/2 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 2/2 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. (Blood. 2015;126(21):2383-2391

Heterogeneous Niche Activity of Ex-Vivo Expanded MSCs as Factor for Variable Outcomes in Hematopoietic Recovery

“…Therefore, ATF4 could be involved by multiple mechanisms for paracrine support of HSCs. Consistent with this, deletion of ATF4 has been shown to lead to deterioration of HSC development and self-renewal with significant impairment of HSC supporting activity in niche cells [65]. Therefore, it is possible that activation of ATF4 signals in MSCs is related to the shift of MSCs towards more activated status reminiscent of the “alert state” of stem cells in response to injury stress [66].…”

tfec controls the hematopoietic stem cell vascular niche during zebrafish embryogenesis

“…33 As well, foxc1 was recently shown to be involved in the expression of cxcl12 from cxcl12-abundant reticulocyte cells in the bone marrow, 34 and ATF4 seems to play a similar role in FL stromal cells. 35 Further understanding of master regulators of the hematopoietic niche will provide additional and more efficient ways to achieve ex vivo HSC expansion.…”

The unfolded protein response in metazoan development

“…Atf4-knockout mice show a few additional tissue phenotypes, including defects in the lens, growth retardation and anemia (Tanaka et al, 1998;Hettmann et al, 2000;Masuoka and Townes, 2002;Zhao et al, 2015). How could ATF4 regulate general animal development?…”