The cellular and molecular components of the niche for hematopoietic stem cells (HSCs) are still not well defined. Angiopoietin-like proteins (Angptls) are a group of secreted glycoproteins that have been reported to play various roles, including the regulation of HSC activity. 1 Specifically, Angptl2, a member of the Angptl family, was demonstrated to support HSC stemness through binding to inhibitory receptors. 2 Angptl2 has also been shown to support HSC activity in exosomes. 3 However, whether and how Angptl2 regulates HSC activities in the HSC niche were still unknown.Yu et al used an elegant approach to study these questions. 1 Based on the expression pattern of Angptl2 in bone marrow, several conditional knockout (KO) mice were generated to deplete Angptl2 from endothelial, mesenchymal stromal cells, megakaryocytes, and HSCs. Using a number of functional assays, including reconstitution analysis, flow cytometry, and immunofluorescence microscopy, the authors discovered that only endothelial cell-derived Angptl2 but not Angptl2 from other niche cell types supported the repopulation capacity, quiescent status, and niche localization of HSCs. They further demonstrated that Angptl2 enhances peroxisome-proliferatoractivated receptor D expression to transactivate G0s2 and sustain the perinuclear localization of nucleolin that prevents HSCs from entering the cell cycle.This study has clarified sustained questions about the physiological role of Angptl2 in regulating HSC activity. It suggests that Angptl2 is indeed a molecular component in the endothelial niche of HSCs that inhibits differentiation and preserves the stemness of stem cells.This study also elicits additional questions. The obvious follow-up questions include what is the detailed mechanism by which the extracellular Angptl2 regulates HSC activity and why