Thrombopoietin/MPL signaling regulates hematopoietic stem cell quiescence and interaction with the osteoblastic niche

Maintenance of hematopoietic stem cells (HSCs) depends on interaction with their niche. Here we show that the long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, MPL, are a quiescent population in adult bone marrow (BM) and are closely associated with THPO-producing osteoblastic cells...

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Published in:Cell stem cell 2007-12, Vol.1 (6), p.685-697
Main Authors: Yoshihara, Hiroki, Arai, Fumio, Hosokawa, Kentaro, Hagiwara, Tetsuya, Takubo, Keiyo, Nakamura, Yuka, Gomei, Yumiko, Iwasaki, Hiroko, Matsuoka, Sahoko, Miyamoto, Kana, Miyazaki, Hiroshi, Takahashi, Takao, Suda, Toshio
Format: Article
Language:English
Subjects:
Animals
Cell Line
Cyclin-Dependent Kinase Inhibitor Proteins - metabolism
Hematopoietic Stem Cells - drug effects
Hematopoietic Stem Cells - physiology
Humans
Integrin beta1 - metabolism
Interphase
Mice
Osteoblasts - physiology
Receptors, Thrombopoietin - metabolism
Signal Transduction
Thrombopoietin - pharmacology
Thrombopoietin - physiology
Up-Regulation
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Summary:Maintenance of hematopoietic stem cells (HSCs) depends on interaction with their niche. Here we show that the long-term (LT)-HSCs expressing the thrombopoietin (THPO) receptor, MPL, are a quiescent population in adult bone marrow (BM) and are closely associated with THPO-producing osteoblastic cells. THPO/MPL signaling upregulated beta1-integrin and cyclin-dependent kinase inhibitors in HSCs. Furthermore, inhibition and stimulation of THPO/MPL pathway by treatments with anti-MPL neutralizing antibody, AMM2, and with THPO showed reciprocal regulation of quiescence of LT-HSC. AMM2 treatment reduced the number of quiescent LT-HSCs and allowed exogenous HSC engraftment without irradiation. By contrast, exogenous THPO transiently increased quiescent HSC population and subsequently induced HSC proliferation in vivo. Altogether, these observations suggest that THPO/MPL signaling plays a critical role of LT-HSC regulation in the osteoblastic niche.
ISSN:1934-5909
1875-9777
DOI:10.1016/j.stem.2007.10.020