title: Integrin-αvβ3 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells.
abstract: 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.
authors.affiliation: Institute of Advanced Biomedical Engineering and Science, Tokyo Women's Medical University, Tokyo, Japan.
authors.forename: Terumasa
authors.initials: T
authors.lastname: Umemoto
authors.forename: Masayuki
authors.initials: M
authors.lastname: Yamato
authors.forename: Jun
authors.initials: J
authors.lastname: Ishihara
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Shiratsuchi
authors.forename: Mika
authors.initials: M
authors.lastname: Utsumi
authors.forename: Yohei
authors.initials: Y
authors.lastname: Morita
authors.forename: Hiroko
authors.initials: H
authors.lastname: Tsukui
authors.forename: Masao
authors.initials: M
authors.lastname: Terasawa
authors.forename: Takehiko
authors.initials: T
authors.lastname: Shibata
authors.forename: Kohji
authors.initials: K
authors.lastname: Nishida
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Kobayashi
authors.forename: Brian G
authors.initials: BG
authors.lastname: Petrich
authors.forename: Hiromitsu
authors.initials: H
authors.lastname: Nakauchi
authors.forename: Koji
authors.initials: K
authors.lastname: Eto
authors.forename: Teruo
authors.initials: T
authors.lastname: Okano
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D015153:Blotting, Western; D001853:Bone Marrow / Q000187:drug effects / Q000378:metabolism; D002450:Cell Communication / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D005260:Female; D005434:Flow Cytometry; D020869:Gene Expression Profiling; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D039302:Integrin alphaVbeta3 / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D015398:Signal Transduction; D013926:Thrombopoietin / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D039302:Integrin alphaVbeta3; D013926:Thrombopoietin
references.citation: J Exp Med. 2000 Nov 6;192(9):1281-8
references.pmid: 11067877
references.citation: Biochem Soc Trans. 2004 Jun;32(Pt3):443-6
references.pmid: 15157156
references.citation: Blood. 2005 Dec 1;106(12):3988-94
references.pmid: 16091451
references.citation: Immunity. 2002 Apr;16(4):547-58
references.pmid: 11970878
references.citation: Science. 2003 Oct 3;302(5642):103-6
references.pmid: 14526080
references.citation: Blood. 2007 Aug 1;110(3):851-9
references.pmid: 17412889
references.citation: Histochem Cell Biol. 1997 Apr;107(4):313-20
references.pmid: 9151113
references.citation: Proc Natl Acad Sci U S A. 1998 Feb 3;95(3):1195-200
references.pmid: 9448308
references.citation: Genes Dev. 2004 Oct 1;18(19):2336-41
references.pmid: 15371326
references.citation: Genes Dev. 2006 Aug 1;20(15):2018-23
references.pmid: 16882979
references.citation: J Cell Biol. 2002 Apr 15;157(2):265-75
references.pmid: 11940607
references.citation: J Biol Chem. 1996 Sep 6;271(36):21745-51
references.pmid: 8702970
references.citation: Cell. 2005 Jul 1;121(7):1109-21
references.pmid: 15989959
references.citation: J Biol Chem. 2004 Oct 22;279(43):44897-906
references.pmid: 15304494
references.citation: J Biol Chem. 1994 Jan 14;269(2):960-7
references.pmid: 7507113
references.citation: J Clin Invest. 2001 May;107(9):1137-44
references.pmid: 11342577
references.citation: Blood. 2009 Feb 5;113(6):1250-6
references.pmid: 18945958
references.citation: Stem Cells. 2008 Mar;26(3):646-55
references.pmid: 18079432
references.citation: Exp Hematol. 1993 Feb;21(2):206-19
references.pmid: 8425559
references.citation: Cell Stem Cell. 2007 Sep 13;1(3):324-37
references.pmid: 18371366
references.citation: J Exp Med. 2008 Sep 29;205(10):2381-95
references.pmid: 18779349
references.citation: Proc Natl Acad Sci U S A. 1990 Nov;87(22):8736-40
references.pmid: 2247442
references.citation: Blood. 1998 Jul 1;92(1):4-10
references.pmid: 9639492
references.citation: Cell. 2002 Sep 20;110(6):673-87
references.pmid: 12297042
references.citation: Cell. 2009 Apr 17;137(2):369-79
references.pmid: 19379700
references.citation: Blood. 1996 Aug 1;88(3):803-8
references.pmid: 8704234
references.citation: Blood. 2000 Apr 1;95(7):2284-8
references.pmid: 10733497
references.citation: Science. 2010 Jan 15;327(5963):340-3
references.pmid: 20075254
references.citation: Cell. 2004 Jul 23;118(2):149-61
references.pmid: 15260986
references.citation: Mol Cell Biol. 2004 Aug;24(15):6751-62
references.pmid: 15254242
references.citation: Curr Opin Cell Biol. 2005 Oct;17(5):509-16
references.pmid: 16099636
references.citation: Thromb Haemost. 1995 Jul;74(1):521-5
references.pmid: 8578518
references.citation: Cell Stem Cell. 2007 Dec 13;1(6):685-97
references.pmid: 18371409
references.citation: Biochem Biophys Res Commun. 2008 Jan 4;365(1):176-82
references.pmid: 17983596
references.citation: Nat Med. 2006 Jun;12(6):657-64
references.pmid: 16715089
references.citation: J Cell Biol. 2009 Jan 12;184(1):57-66
references.pmid: 19139262
references.citation: Cell Stem Cell. 2007 Dec 13;1(6):671-84
references.pmid: 18371408
references.citation: J Biol Chem. 2005 Aug 19;280(33):29699-707
references.pmid: 15937333
references.citation: Blood. 2005 Jul 15;106(2):494-504
references.pmid: 15784726
references.citation: Blood. 2005 Aug 15;106(4):1232-9
references.pmid: 15845900
references.citation: J Cell Biol. 1998 Oct 5;143(1):241-52
references.pmid: 9763435
references.citation: Proc Natl Acad Sci U S A. 1988 Oct;85(20):7734-8
references.pmid: 2971974
references.citation: Blood. 1996 Mar 15;87(6):2162-70
references.pmid: 8630375
references.citation: J Clin Invest. 2010 Jan;120(1):179-90
references.pmid: 20038804
references.citation: J Clin Invest. 2007 Aug;117(8):2250-9
references.pmid: 17627302
references.citation: J Immunol. 2006 Dec 1;177(11):7733-9
references.pmid: 17114444