Endothelial cell-derived angiopoietin-like protein 2 supports hematopoietic stem cell activities in bone marrow niches

Abstract

Bone marrow niche cells have been reported to fine-tune HSC stemness via direct interaction or secreted components. Nevertheless, how niche cells control HSC activities remains largely unknown. We previously showed that angiopoietin-like protein 2 (ANGPTL2) can support the ex vivo expansion of HSCs by binding to human leukocyte immunoglobulin-like receptor B2 (LILRB2). However, how ANGPTL2 from specific niche cell types regulates HSC activities under physiological conditions is still not clear. Herein, we generated an Angptl2-flox/flox transgenic mouse line and conditionally deleted Angptl2 expression in several niche cells, including Cdh5+ or Tie2+ endothelial cells, Prx1+ mesenchymal stem cells and Pf4+ megakaryocytes, to evaluate its role in the regulation of HSC fate. Interestingly, we demonstrated that only endothelial cell-derived ANGPTL2 and not ANGPTL2 from other niche cell types plays important roles in supporting repopulation capacity, quiescent status and niche localization. Mechanistically, ANGPTL2 enhances PPARD expression to transactivate G0s2 to sustain the perinuclear localization of nucleolin to prevent HSCs from entering the cell cycle. These findings reveal that endothelial cell-derived ANGPTL2 serves as a critical niche component to maintain HSC stemness, which may benefit the understanding of stem cell biology in bone marrow niches and the development of a unique strategy for the ex vivo expansion of HSCs.

New Insights into Hematopoietic Stem Cell Expansion to Stimulate Repopulation of the Adult Blood System for Transplantation

“…To measure the self-renewal ability of SRCs, the SCID-SRCs are transplanted into the non-obese diabetic SCID (NOD/SCID) mice. Results of the study showed that a serum-free culture including SCF, THPO and FGF-1 or Flt3-L cannot clearly amplify SRCs present in human cord blood CD133 cells [ 73 ]. However, when either angiopoietin-like protein 5 or IGF-binding protein 2 is included in the experiment, the expansion of HSCs becomes significant.…”

Angiocrine ANGPTL2 executes HSC functions in endothelial niche

“…In this issue of Blood, Yu et al demonstrate that angiopoietin-like 2 (ANGPTL2) secreted by the vascular niche endothelial cells serves as the seminal paracrine angiocrine factor, orchestrating hematopoietic stem cell (HSC) homeostasis and regeneration after myelosuppression. 1 Tissue-specific endothelium, such as BM endothelial cells (BMECs), is endowed with unique organotypic specialized functions, including modulation of metabolism, immune cell trafficking, inflammatory response, vascular tone, regeneration, and repair. 2,3 It is well documented that blood vessels in the BM are not just passive conduits delivering nutrients and oxygen to hematopoietic cells.…”

An old player, the right niche

“…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 .…”

“…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.…”

“…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.…”