| 1. |
Arai F, Yoshihara H, Hosokawa K, Nakamura Y, Gomei Y, Iwasaki H, Suda T., Niche regulation of hematopoietic stem cells in the endosteum., Ann N Y Acad Sci, 1176:36-46, 2009.05, 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, Mpl, as a quiescent population in adult BM. THPO was produced by bone-lining cells in the endosteum. Inhibition and stimulation of the THPO/Mpl 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-Mpl neutralizing antibody, AMM2, suppressed the quiescence of LT-HSCs and enabled HSC engraftment without irradiation, indicating that inhibition of THPO/Mpl 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/Mpl 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.. |
| 2. |
Arai F, Hosokawa K, Toyama H, Matsumoto Y, Suda T., Role of N-cadherin in the regulation of hematopoietic stem cells in the bone marrow niche., Ann N Y Acad Sci., 10.1111/j.1749-6632.2012.06576.x., 1266 (1): 72-77, 2012.08, Cell-cell and cell-extracellular matrix interactions between hematopoietic stem cells (HSCs) and their niches are critical for the maintenance of stem cell properties. Here, it is demonstrated that a cell adhesion molecule, N-cadherin, is expressed in hematopoietic stem/progenitor cells (HSPCs) and plays a critical role in the regulation of HSPC engraftment. Furthermore, overexpression of N-cadherin in HSCs promoted quiescence and preserved HSC activity during serial bone marrow (BM) transplantation (BMT). Inhibition of N-cadherin by the transduction of N-cadherin short hairpin (sh) RNA (shN-cad) reduced the lodgment of donor HSCs to the endosteal surface, resulting in a significant reduction in long-term engraftment. shN-cad-transduced cells were maintained in the spleen for six months after BMT, indicating that N-cadherin expression in HSCs is specifically required in the BM. These findings suggest that N-cadherin-mediated cell adhesion is functionally essential for the regulation of HSPC activities in the BM niche.. |
| 3. |
Arai F, Hosokawa K, Matsumoto Y, Toyama H, Suda T., Network analysis in systems biology.
Gene expression profiling and regulatory networks in single cell. Network analysis in systems biology., Springer International Publishing AG., pp. 1-13
ISBN 978-94-007-4330-4, 2012.01. |
