Several studies have indicated that transforming growth factor β (TGF-β) is a critical regulator of HSC quiescence. 3, 4 Despite significant progress, the mechanisms that regulate HSC activation and their self-renewal are still not entirely understood. 3 However, during stress conditions, such as bone marrow (BM) transplantation or chemotherapy, LT-HSCs exit the quiescent state and proliferate to provide new blood cells and to replenish the hematopoietic stem cell (HSC) pool. Under normal conditions, the majority of bone marrow LT-HSCs are in a quiescent state that is characterized by slow cell cycling or G 0 phase, 1, 2 dividing only ∼5 times per lifespan. Long-term hematopoietic stem cells (LT-HSCs) are responsible for lifelong blood production. These findings support an essential role for Eng in positively modulating TGF-β signaling to ensure maintenance of HSC quiescence. Using cytometry by time of flight (CyTOF) to evaluate the activity of signaling pathways in individual HSCs, we find that Eng is required within the Lin −Sca +Kit +–CD48 − CD150 + fraction for canonical and noncanonical TGF-β signaling, as indicated by decreased phosphorylation of SMAD2/3 and the p38 MAPK-activated protein kinase 2, respectively. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G 0, suggesting that lack of Eng impairs reentry of HSCs to quiescence.
Transplantation of Eng-deleted whole bone marrow or purified HSCs into lethally irradiated mice results in a profound engraftment defect in tertiary and quaternary recipients. Using conditional deletion of Eng combined with serial transplantation, we show that this TGF-β receptor is critical to maintain the HSC pool. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark long-term HSCs however, its necessity in adult HSCs is unknown due to embryonic lethality. However, the molecular mechanism underlining this function remains obscure. Transforming growth factor β (TGF-β) is well known for its important function in hematopoietic stem cell (HSC) quiescence.
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