OKANO Teruo    Department   Research Institutes and Facilities, Research Institutes and Facilities    Position
Article types	Original article
Language	English
Peer review	Non peer reviewed
Title	Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells.
Journal	Formal name：Blood Abbreviation：Blood ISSN code：(1528-0020)0006-4971(Linking)
Domestic / Foregin	Foregin
Volume, Issue, Page	119(1),pp.83-94
Author and coauthor	Umemoto Terumasa†, Yamato Masayuki*, Ishihara Jun, Shiratsuchi Yoshiko, Utsumi Mika, Morita Yohei, Tsukui Hiroko, Terasawa Masao, Shibata Takehiko, Nishida Kohji, Kobayashi Yoshiro, Petrich Brian G, Nakauchi Hiromitsu, Eto Koji*, Okano Teruo
Authorship	Last author
Publication date	2012/01
Summary	Throughout life, one's blood supply depends on sustained division of hematopoietic stem cells (HSCs) for self-renewal and differentiation. Within the bone marrow microenvironment, an adhesion-dependent or -independent niche system regulates HSC function. Here we show that a novel adhesion-dependent mechanism via integrin-β3 signaling contributes to HSC maintenance. Specific ligation of β3-integrin on HSCs using an antibody or extracellular matrix protein prevented loss of long-term repopulating (LTR) activity during ex vivo culture. The actions required activation of αvβ3-integrin "inside-out" signaling, which is dependent on thrombopoietin (TPO), an essential cytokine for activation of dormant HSCs. Subsequent "outside-in" signaling via phosphorylation of Tyr747 in the β3-subunit cytoplasmic domain was indispensable for TPO-dependent, but not stem cell factor-dependent, LTR activity in HSCs in vivo. This was accompanied with enhanced expression of Vps72, Mll1, and Runx1, 3 factors known to be critical for maintaining HSC activity. Thus, our findings demonstrate a mechanistic link between β3-integrin and TPO in HSCs, which may contribute to maintenance of LTR activity in vivo as well as during ex vivo culture.
DOI	10.1182/blood-2011-02-335430
PMID	22096247