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. 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.
Yoshihara
Hiroki
H
Department of Cell Differentiation, The Sakaguchi Laboratory of Developmental Biology, Keio University, 35 Shinano-machi, Tokyo, 160-8582, Japan.
Arai
Fumio
F
Hosokawa
Kentaro
K
Hagiwara
Tetsuya
T
Takubo
Keiyo
K
Nakamura
Yuka
Y
Gomei
Yumiko
Y
Iwasaki
Hiroko
H
Matsuoka
Sahoko
S
Miyamoto
Kana
K
Miyazaki
Hiroshi
H
Takahashi
Takao
T
Suda
Toshio
T
D000818:Animals; D002460:Cell Line; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000378:metabolism; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D007399:Interphase; D051379:Mice; D010006:Osteoblasts / Q000502:physiology*; D053628:Receptors, Thrombopoietin / Q000378:metabolism*; D015398:Signal Transduction; D013926:Thrombopoietin / Q000494:pharmacology / Q000502:physiology*; D015854:Up-Regulation
D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D019012:Integrin beta1; D053628:Receptors, Thrombopoietin; D013926:Thrombopoietin