{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2023,9,13]],"date-time":"2023-09-13T19:51:04Z","timestamp":1694634664018},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"5","license":[{"start":{"date-parts":[[2009,2,20]],"date-time":"2009-02-20T00:00:00Z","timestamp":1235088000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2009,5,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>The Rho GTPase family members play essential roles in hematopoiesis. Of these, Rac1 is thought to be required for the appropriate spatial localization of hematopoietic stem and\/or progenitor cells (HSPCs) within the bone marrow (BM), whereas Rac2 likely plays a role in BM retention of HSPCs. To elucidate the molecular mechanisms underlying Rac-mediated functions in hematopoietic stem cells (HSCs), we studied Wiskott-Aldrich syndrome protein family verprolin-homologous proteins (WAVEs), the specific effectors downstream of the Rac GTPases in actin polymerization. We here showed that CD34\u2212\/lowc-Kit+Sca-1+lineage\u2212 HSCs (CD34\u2212KSL HSCs) express WAVE2 but neither WAVE1 nor WAVE3. Because WAVE2 knockout mice are embryonic-lethal, we utilized HSCs in which the expression of WAVE2 was reduced by small interfering RNA. We found that knockdown (KD) of WAVE2 in HSCs affected neither in vitro colony formation nor cell proliferation but did impair in vivo long-term reconstitution. Interestingly, WAVE2 KD HSCs exhibited unaltered homing but showed poor BM repopulation detected as early as day 5 after transplantation. The mechanistic studies on WAVE2 KD HSCs revealed modest but significant impairment in both cobblestone-like area-forming on stromal layers and actin polymerization upon integrin ligation by fibronectin. These results suggested that WAVE2-mediated actin polymerization, potentially downstream of Rac1, plays an important role in intramarrow mobilization and proliferation of HSCs, which are believed to be crucial steps for long-term marrow reconstitution after transplantation.<\/jats:p>\n               <jats:p>Disclosure of potential conflicts of interest is found at the end of this article.<\/jats:p>","DOI":"10.1002\/stem.42","type":"journal-article","created":{"date-parts":[[2009,2,20]],"date-time":"2009-02-20T18:40:44Z","timestamp":1235155244000},"page":"1120-1129","source":"Crossref","is-referenced-by-count":15,"title":["The Actin Polymerization Regulator WAVE2 Is Required for Early Bone Marrow Repopulation by Hematopoietic Stem Cells"],"prefix":"10.1093","volume":"27","author":[{"given":"Takunori","family":"Ogaeri","sequence":"first","affiliation":[{"name":"Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Koji","family":"Eto","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Otsu","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hideo","family":"Ema","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hiromitsu","family":"Nakauchi","sequence":"additional","affiliation":[{"name":"Division of Stem Cell Therapy, Center for Stem Cell and Regenerative Medicine, The Institute of Medical Science, University of Tokyo, Tokyo, Japan"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2009,2,20]]},"reference":[{"key":"2022011221391625900_bib1","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/ni1331","article-title":"The hematopoietic stem cell in its place","volume":"7","author":"Adams","year":"2006","journal-title":"Nat Immunol"},{"key":"2022011221391625900_bib2","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/978-0-387-72009-8_8","article-title":"Regulation of hematopoietic stem cells in the osteoblastic niche","volume":"602","author":"Arai","year":"2007","journal-title":"Adv Exp Med Biol"},{"key":"2022011221391625900_bib3","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1038\/nri2279","article-title":"Uncertainty in the niches that maintain haematopoietic stem cells","volume":"8","author":"Kiel","year":"2008","journal-title":"Nat Rev Immunol"},{"key":"2022011221391625900_bib4","doi-asserted-by":"crossref","first-page":"1075","DOI":"10.1038\/nature04957","article-title":"The stem-cell niche as an entity of action","volume":"441","author":"Scadden","year":"2006","journal-title":"Nature"},{"key":"2022011221391625900_bib5","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1007\/978-0-387-72009-8_9","article-title":"The chemokine CXCL12 and regulation of HSC and B lymphocyte development in the bone marrow niche","volume":"602","author":"Nagasawa","year":"2007","journal-title":"Adv Exp Med Biol"},{"key":"2022011221391625900_bib6","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1016\/j.immuni.2006.11.005","article-title":"Maintaining hematopoietic stem cells in the vascular niche","volume":"25","author":"Kiel","year":"2006","journal-title":"Immunity"},{"key":"2022011221391625900_bib7","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1038\/nature04247","article-title":"Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor","volume":"439","author":"Adams","year":"2006","journal-title":"Nature"},{"key":"2022011221391625900_bib8","doi-asserted-by":"crossref","first-page":"238","DOI":"10.1038\/nbt1281","article-title":"Therapeutic targeting of a stem cell niche","volume":"25","author":"Adams","year":"2007","journal-title":"Nat Biotechnol"},{"key":"2022011221391625900_bib9","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.beha.2006.11.001","article-title":"The stem cell niche in health and leukemic disease","volume":"20","author":"Scadden","year":"2007","journal-title":"Best Pract Res Clin Haematol"},{"issue":"Part 5","key":"2022011221391625900_bib10","doi-asserted-by":"crossref","first-page":"891","DOI":"10.1042\/BST0330891","article-title":"Rho GTPases and the control of cell behaviour","volume":"33","author":"Hall","year":"2005","journal-title":"Biochem Soc Trans"},{"key":"2022011221391625900_bib11","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1038\/nrm2069","article-title":"The WASp-WAVE protein network: Connecting the membrane to the cytoskeleton","volume":"8","author":"Takenawa","year":"2007","journal-title":"Nat Rev Mol Cell Biol"},{"key":"2022011221391625900_bib12","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1016\/S0092-8674(03)00120-X","article-title":"Cellular motility driven by assembly and disassembly of actin filaments","volume":"112","author":"Pollard","year":"2003","journal-title":"Cell"},{"key":"2022011221391625900_bib13","doi-asserted-by":"crossref","first-page":"6932","DOI":"10.1093\/emboj\/17.23.6932","article-title":"WAVE, a novel WASp-family protein involved in actin reorganization induced by Rac","volume":"17","author":"Miki","year":"1998","journal-title":"EMBO J"},{"key":"2022011221391625900_bib14","doi-asserted-by":"crossref","first-page":"976","DOI":"10.1016\/j.exphem.2006.03.016","article-title":"The role of chemokine activation of Rac GTPases in hematopoietic stem cell marrow homing, retention, and peripheral mobilization","volume":"34","author":"Cancelas","year":"2006","journal-title":"Exp Hematol"},{"key":"2022011221391625900_bib15","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/nm1274","article-title":"Rac GTPases differentially integrate signals regulating hematopoietic stem cell localization","volume":"11","author":"Cancelas","year":"2005","journal-title":"Nat Med"},{"key":"2022011221391625900_bib16","doi-asserted-by":"crossref","first-page":"445","DOI":"10.1126\/science.1088485","article-title":"Hematopoietic cell regulation by Rac1 and Rac2 guanosine triphosphatases","volume":"302","author":"Gu","year":"2003","journal-title":"Science"},{"key":"2022011221391625900_bib17","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1126\/science.273.5272.242","article-title":"Long-term lymphohematopoietic reconstitution by a single CD34-low\/negative hematopoietic stem cell","volume":"273","author":"Osawa","year":"1996","journal-title":"Science"},{"key":"2022011221391625900_bib18","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1073\/pnas.232688199","article-title":"Inhibiting HIV-1 infection in human T cells by lentiviral-mediated delivery of small interfering RNA against CCR5","volume":"100","author":"Qin","year":"2003","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022011221391625900_bib19","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/S1534-5807(03)00297-1","article-title":"Differential roles of WAVE1 and WAVE2 in dorsal and peripheral ruffle formation for fibroblast cell migration","volume":"5","author":"Suetsugu","year":"2003","journal-title":"Dev Cell"},{"key":"2022011221391625900_bib20","doi-asserted-by":"crossref","first-page":"3637","DOI":"10.1182\/blood-2007-04-085860","article-title":"The WAVE2\/Abi1 complex differentially regulates megakaryocyte development and spreading: implications for platelet biogenesis and spreading machinery","volume":"110","author":"Eto","year":"2007","journal-title":"Blood"},{"key":"2022011221391625900_bib21","doi-asserted-by":"crossref","first-page":"2769","DOI":"10.1182\/blood-2002-01-0182","article-title":"Erythroid expansion mediated by the Gfi-1B zinc finger protein: Role in normal hematopoiesis","volume":"100","author":"Osawa","year":"2002","journal-title":"Blood"},{"key":"2022011221391625900_bib22","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1038\/nprot.2006.447","article-title":"Adult mouse hematopoietic stem cells: Purification and single-cell assays","volume":"1","author":"Ema","year":"2006","journal-title":"Nat Protoc"},{"key":"2022011221391625900_bib23","doi-asserted-by":"crossref","first-page":"3515","DOI":"10.1038\/sj.emboj.7601236","article-title":"Cytokine signals modulated via lipid rafts mimic niche signals and induce hibernation in hematopoietic stem cells","volume":"25","author":"Yamazaki","year":"2006","journal-title":"EMBO J"},{"key":"2022011221391625900_bib24","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/nature01770","article-title":"WAVE2 is required for directed cell migration and cardiovascular development","volume":"424","author":"Yamazaki","year":"2003","journal-title":"Nature"},{"key":"2022011221391625900_bib25","doi-asserted-by":"crossref","first-page":"1281","DOI":"10.1084\/jem.192.9.1281","article-title":"In vitro self-renewal division of hematopoietic stem cells","volume":"192","author":"Ema","year":"2000","journal-title":"J Exp Med"},{"key":"2022011221391625900_bib26","doi-asserted-by":"crossref","first-page":"907","DOI":"10.1016\/j.devcel.2005.03.019","article-title":"Quantification of self-renewal capacity in single hematopoietic stem cells from normal and Lnk-deficient mice","volume":"8","author":"Ema","year":"2005","journal-title":"Dev Cell"},{"key":"2022011221391625900_bib27","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1111\/j.1538-7836.2004.01082.x","article-title":"Expression and subcellular localization of WAVE isoforms in the megakaryocyte\/platelet lineage","volume":"3","author":"Kashiwagi","year":"2005","journal-title":"J Thromb Haemost"},{"key":"2022011221391625900_bib28","doi-asserted-by":"crossref","first-page":"3141","DOI":"10.1182\/blood-2003-04-1319","article-title":"WAVE\/scars in platelets","volume":"105","author":"Oda","year":"2005","journal-title":"Blood"},{"key":"2022011221391625900_bib29","doi-asserted-by":"crossref","first-page":"39474","DOI":"10.1074\/jbc.M504672200","article-title":"Rac1 is essential for platelet lamellipodia formation and aggregate stability under flow","volume":"280","author":"McCarty","year":"2005","journal-title":"J Biol Chem"},{"key":"2022011221391625900_bib30","doi-asserted-by":"crossref","first-page":"5091","DOI":"10.1073\/pnas.0610819104","article-title":"Rho GTPase Cdc42 coordinates hematopoietic stem cell quiescence and niche interaction in the bone marrow","volume":"104","author":"Yang","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"2022011221391625900_bib31","doi-asserted-by":"crossref","first-page":"3853","DOI":"10.1182\/blood-2007-03-079582","article-title":"Cdc42 critically regulates the balance between myelopoiesis and erythropoiesis","volume":"110","author":"Yang","year":"2007","journal-title":"Blood"},{"key":"2022011221391625900_bib32","doi-asserted-by":"crossref","first-page":"2087","DOI":"10.1182\/blood-2006-02-001560","article-title":"Inhibition of RhoA GTPase activity enhances hematopoietic stem and progenitor cell proliferation and engraftment","volume":"108","author":"Ghiaur","year":"2006","journal-title":"Blood"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fstem.42","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/stem.42","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/stem.42","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/27\/5\/1120\/41947322\/stmcls_27_5_1120.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/27\/5\/1120\/41947322\/stmcls_27_5_1120.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,19]],"date-time":"2022-01-19T03:05:04Z","timestamp":1642561504000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/27\/5\/1120-1129\/6402195"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2009,2,20]]},"references-count":32,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2009,2,20]]},"published-print":{"date-parts":[[2009,5,1]]}},"URL":"https:\/\/doi.org\/10.1002\/stem.42","relation":{},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2009,5,1]]},"published":{"date-parts":[[2009,2,20]]}}}