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Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence

Borges, L, Oliveira, V.K.P., Baik, J. et al.

TGF-β is well-known for its important function in hematopoietic stem cell (HSC) quiescence. However the molecular mechanism underlining this function remains obscure. Endoglin (Eng), a type III receptor for the TGF-β superfamily, has been shown to selectively mark the long-term HSC, however its necessity in adult HSC is unknown due to embryonic lethality. Using conditional deletion of Eng combined with serial transplantation, here we show that this TGF-β receptor is critical to maintain the HSC pool. 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. Cell cycle analysis of primary grafts revealed decreased frequency of HSCs in G0, suggesting that lack of Eng impairs re-entry of HSCs to quiescence. Using CyTOF to evaluate activity of signaling pathways in individual HSCs, we find that endoglin is required within the LSK-SLAM fraction for both canonical and non-canonical TGF-β signaling, as indicated by decreased phosphorylation of both SMAD2/3 and the p38 MAPK-activated protein kinase 2 (MAPKAPK2), respectively.

Citation

Borges, L, Oliveira, V.K.P., Baik, J. et al. "Serial transplantation reveals a critical role for endoglin in hematopoietic stem cell quiescence" Blood (2018): doi: 10.1182/blood-2018-09-874677