Niche Regulation of Hematopoietic Stem Cells in the Endosteum The Role of Thrombopoietin/Mp1 Signaling in the Maintenance of Quiescent Hematopoietic Stem Cells

During postnatal life, the bone marrow (BM) supports both the self-renewal and differentiation of hematopoietic stem cells (HSCs) in specialized niches. The interaction of HSCs with their niches also regulates the quiescence of HSCs. HSC quiescence is critical to ensure lifelong hematopoiesis and to protect the HSC pool from myelotoxic insult and premature exhaustion under conditions of hematopoietic stress. Here we identified long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, Mp1, as a quiescent population in adult BM. THPO was produced by bone-lining cells in the endosteum. Inhibition and stimulation of the THPO/Mp1 pathway produced opposite effects on the quiescence of LT-HSC. Exogenous THPO transiently increased the quiescent LT-HSC population, such as side-population and pyronin Y-negative cells. In contrast, administration of an anti-Mp1 neutralizing antibody, AMM2, suppressed the quiescence of LT-HSCs and enabled HSC engraftment without irradiation, indicating that inhibition of THPO/Mp1 signaling reduces HSC-niche interactions. Moreover, it suggests that inhibiting the HSC-niche interaction could represent a novel technique for bone marrow transplantation without irradiation. Altogether, these data suggest that the THPO/Mp1 signaling pathway is a novel niche component in the endosteum, and in the steady-state condition, this signaling pathway plays a critical role in the regulation of LT-HSCs in the osteoblastic niche.