SHP-1 regulates hematopoietic stem cell quiescence by coordinating TGF-β signaling

Cell cycle quiescence is critical for hematopoietic stem cell (HSC) maintenance. TGF-beta signaling in bone marrow niche has been identified in regulating HSC quiescence; however, the intrinsic regulatory mechanisms remain unclear. This study reports that Shp-1 knockout HSCs have attenuated quiescence and impaired long-term self-renewal. SHP-1-activated HSCs are surrounded by megakaryocytes, which regulate HSC quiescence by producing TGF-beta 1. Mechanistically, SHP-1 interacts with the immunoreceptor tyrosine-based inhibition motif on TGF-beta receptor 1 and is critical for TGF-ss signaling activation in HSCs. Functionally, Shp-1 knockout HSCs do not respond to TGF-beta-enforced HSC quiescence regulation, both in vitro and in vivo. Therefore, we identify TGF-beta-SHP-1 as a novel intrinsic regulatory mechanism for HSC quiescence maintenance.