The transcription factor ATF4 is essential for HSC self-renewal in the FL. Although the emergence and migration of definitive HSCs are largely independent of the presence of ATF4, the transcription factor is required for the intrinsic and extrinsic regulation of HSC self-renewal during their massive expansion phase between embryonic day 11.5 (E11.5) and E15.5 in the FL. ATF4 activates the expression and secretion of Angptl3 in the FL microenvironment, particularly in endothelial cells (ECs) and stroma cells (SCs), which further promotes the self-renewal of HSCs. AGM, aorta-gonad-mesonephros; WT, wild-type.