{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T03:36:45Z","timestamp":1791344205870,"version":"4.3.1"},"reference-count":37,"publisher":"Oxford University Press (OUP)","issue":"12","license":[{"start":{"date-parts":[[2008,9,11]],"date-time":"2008-09-11T00:00:00Z","timestamp":1221091200000},"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":[[2008,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Hematopoiesis is a dynamic and strictly regulated process orchestrated by self-renewing hematopoietic stem cells (HSCs) and the supporting microenvironment. However, the exact mechanisms by which individual human HSCs sustain hematopoietic homeostasis remain to be clarified. To understand how the long-term repopulating cell (LTRC) activity of individual human HSCs and the hematopoietic hierarchy are maintained in the bone marrow (BM) microenvironment, we traced the repopulating dynamics of individual human HSC clones using viral integration site analysis. Our study presents several lines of evidence regarding the in vivo dynamics of human hematopoiesis. First, human LTRCs existed in a rare population of CD34+CD38\u2212 cells that localized to the stem cell niches and maintained their stem cell activities while being in a quiescent state. Second, clonally distinct LTRCs controlled hematopoietic homeostasis and created a stem cell pool hierarchy by asymmetric self-renewal division that produced lineage-restricted short-term repopulating cells and long-lasting LTRCs. Third, we demonstrated that quiescent LTRC clones expanded remarkably to reconstitute the hematopoiesis of the secondary recipient. Finally, we further demonstrated that human mesenchymal stem cells differentiated into key components of the niche and maintained LTRC activity by closely interacting with quiescent human LTRCs, resulting in more LTRCs. Taken together, this study provides a novel insight into repopulation dynamics, turnover, hierarchical structure, and the cell cycle status of human HSCs in the recipient BM microenvironment.<\/jats:p>\n                  <jats:p>Disclosure of potential conflicts of interest is found at the end of this article.<\/jats:p>","DOI":"10.1634\/stemcells.2008-0552","type":"journal-article","created":{"date-parts":[[2008,9,11]],"date-time":"2008-09-11T21:38:11Z","timestamp":1221169091000},"page":"3228-3236","source":"Crossref","is-referenced-by-count":45,"title":["Quiescent Human Hematopoietic Stem Cells in the Bone Marrow Niches Organize the Hierarchical Structure of Hematopoiesis"],"prefix":"10.1093","volume":"26","author":[{"given":"Takashi","family":"Yahata","sequence":"first","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"},{"name":"Department of Hematology; Tokai University School of Medicine, Kanagawa, Japan"},{"name":"Department of Cell Transplantation and Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukari","family":"Muguruma","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shizu","family":"Yumino","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yin","family":"Sheng","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Uno","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Matsuzawa","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mamoru","family":"Ito","sequence":"additional","affiliation":[{"name":"Central Institute for Experimental Animals, Kawasaki, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shunichi","family":"Kato","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"},{"name":"Department of Cell Transplantation and Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomomitsu","family":"Hotta","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"},{"name":"Department of Hematology; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kiyoshi","family":"Ando","sequence":"additional","affiliation":[{"name":"Division of Hematopoiesis, Research Center for Regenerative Medicine; Tokai University School of Medicine, Kanagawa, Japan"},{"name":"Department of Hematology; Tokai University School of Medicine, Kanagawa, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2008,9,11]]},"reference":[{"key":"2022011315271468000_bib1","doi-asserted-by":"crossref","first-page":"1804","DOI":"10.1126\/science.287.5459.1804","article-title":"Hematopoietic stem cell quiescence maintained by p21cip1\/waf1","volume":"287","author":"Cheng","year":"2000","journal-title":"Science"},{"key":"2022011315271468000_bib2","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1038\/nri1779","article-title":"Bone-marrow haematopoietic-stem-cell niches","volume":"6","author":"Wilson","year":"2006","journal-title":"Nat Rev Immunol"},{"key":"2022011315271468000_bib3","doi-asserted-by":"crossref","first-page":"841","DOI":"10.1038\/nature02040","article-title":"Osteoblastic cells regulate the haematopoietic stem cell niche","volume":"425","author":"Calvi","year":"2003","journal-title":"Nature"},{"key":"2022011315271468000_bib4","doi-asserted-by":"crossref","first-page":"836","DOI":"10.1038\/nature02041","article-title":"Identification of the haematopoietic stem cell niche and control of the niche size","volume":"425","author":"Zhang","year":"2003","journal-title":"Nature"},{"key":"2022011315271468000_bib5","doi-asserted-by":"crossref","first-page":"1109","DOI":"10.1016\/j.cell.2005.05.026","article-title":"SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells","volume":"121","author":"Kiel","year":"2005","journal-title":"Cell"},{"key":"2022011315271468000_bib6","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1038\/nri2017","article-title":"Humanized mice in translational biomedical research","volume":"7","author":"Shultz","year":"2007","journal-title":"Nat Rev Immunol"},{"key":"2022011315271468000_bib7","doi-asserted-by":"crossref","first-page":"5320","DOI":"10.1073\/pnas.94.10.5320","article-title":"Purification of primitive human hematopoietic cells capable of repopulating immune-deficient mice","volume":"94","author":"Bhatia","year":"1997","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011315271468000_bib8","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1073\/pnas.012336799","article-title":"Differential long-term and multilineage engraftment potential from subfractions of human CD34+ cord blood cells transplanted into NOD\/SCID mice","volume":"99","author":"Hogan","year":"2002","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011315271468000_bib9","doi-asserted-by":"crossref","first-page":"3692","DOI":"10.4049\/jimmunol.167.7.3692","article-title":"Both CD34+38+ and CD34+38- cells home specifically to the bone marrow of NOD\/LtSZ scid\/scid mice but show different kinetics in expansion","volume":"167","author":"Kerre","year":"2001","journal-title":"J Immunol"},{"key":"2022011315271468000_bib10","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1172\/JCI11519","article-title":"Previously undetected human hematopoietic cell populations with short-term repopulating activity selectively engraft NOD\/SCID-beta2 microglobulin-null mice","volume":"107","author":"Glimm","year":"2001","journal-title":"J Clin Invest"},{"key":"2022011315271468000_bib11","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/83199","article-title":"Distinct classes of human stem cells that differ in proliferative and self-renewal potential","volume":"2","author":"Guenechea","year":"2001","journal-title":"Nat Immunol"},{"key":"2022011315271468000_bib12","doi-asserted-by":"crossref","first-page":"2446","DOI":"10.1182\/blood-2006-02-002204","article-title":"Clonal analysis of thymus-repopulating cells presents direct evidence for self-renewal division of human hematopoietic stem cells","volume":"108","author":"Yahata","year":"2006","journal-title":"Blood"},{"key":"2022011315271468000_bib13","doi-asserted-by":"crossref","first-page":"204","DOI":"10.4049\/jimmunol.169.1.204","article-title":"Functional human T lymphocyte development from cord blood CD34+ cells in nonobese diabetic\/Shi-scid, IL-2 Receptor Gamma Null Mice","volume":"169","author":"Yahata","year":"2002","journal-title":"J Immunol"},{"key":"2022011315271468000_bib14","doi-asserted-by":"crossref","first-page":"3175","DOI":"10.1182\/blood-2001-12-0207","article-title":"NOD\/SCID\/gamma(c)(null) mouse: An excellent recipient mouse model for engraftment of human cells","volume":"100","author":"Ito","year":"2002","journal-title":"Blood"},{"key":"2022011315271468000_bib15","doi-asserted-by":"crossref","first-page":"1878","DOI":"10.1182\/blood-2005-06-2211","article-title":"Reconstitution of the functional human hematopoietic microenvironment derived from human mesenchymal stem cells in the murine bone marrow compartment","volume":"107","author":"Muguruma","year":"2006","journal-title":"Blood"},{"key":"2022011315271468000_bib16","doi-asserted-by":"crossref","first-page":"2293","DOI":"10.1182\/blood.V97.8.2293","article-title":"Spatial localization of transplanted hemopoietic stem cells: Inferences for the localization of stem cell niches","volume":"97","author":"Nilsson","year":"2001","journal-title":"Blood"},{"key":"2022011315271468000_bib17","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1016\/j.immuni.2006.10.016","article-title":"Maintenance of the hematopoietic stem cell pool by CXCL12-CXCR4 chemokine signaling in bone marrow stromal cell niches","volume":"25","author":"Sugiyama","year":"2006","journal-title":"Immunity"},{"key":"2022011315271468000_bib18","first-page":"1347","article-title":"High-resolution cell cycle analysis of defined phenotypic subsets within primitive human hematopoietic cell populations","volume":"24","author":"Jordan","year":"1996","journal-title":"Exp Hematol"},{"key":"2022011315271468000_bib19","doi-asserted-by":"crossref","first-page":"3745","DOI":"10.1182\/blood.V86.10.3745.bloodjournal86103745","article-title":"A functional comparison of CD34+ CD38- cells in cord blood and bone marrow","volume":"86","author":"Hao","year":"1995","journal-title":"Blood"},{"key":"2022011315271468000_bib20","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1182\/blood.V92.8.2641","article-title":"Cell cycle-related changes in repopulating capacity of human mobilized peripheral blood CD34(+) cells in non-obese diabetic\/severe combined immune-deficient mice","volume":"92","author":"Gothot","year":"1998","journal-title":"Blood"},{"key":"2022011315271468000_bib21","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1634\/stemcells.19-6-505","article-title":"Cord blood G(0) CD34+ cells have a thousand-fold higher capacity for generating progenitors in vitro than G(1) CD34+ cells","volume":"19","author":"Summers","year":"2001","journal-title":"Stem Cells"},{"key":"2022011315271468000_bib22","doi-asserted-by":"crossref","first-page":"561","DOI":"10.1634\/stemcells.2004-0060","article-title":"Cycling G1 CD34+\/CD38+ cells potentiate the motility and engraftment of quiescent G0 CD34+\/CD38-\/low severe combined immunodeficiency repopulating cells","volume":"23","author":"Byk","year":"2005","journal-title":"Stem Cells"},{"key":"2022011315271468000_bib23","doi-asserted-by":"crossref","first-page":"1062","DOI":"10.1634\/stemcells.2006-0528","article-title":"Hemopoietic stem cells with higher hemopoietic potential reside at the bone marrow endosteum","volume":"25","author":"Haylock","year":"2007","journal-title":"Stem Cells"},{"key":"2022011315271468000_bib24","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1016\/j.cell.2004.07.004","article-title":"Tie2\/angiopoietin-1 signaling regulates hematopoietic stem cell quiescence in the bone marrow niche","volume":"118","author":"Arai","year":"2004","journal-title":"Cell"},{"key":"2022011315271468000_bib25","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/nm886","article-title":"Rapid myeloerythroid repopulation after intrafemoral transplantation of NOD-SCID mice reveals a new class of human stem cells","volume":"9","author":"Mazurier","year":"2003","journal-title":"Nat Med"},{"key":"2022011315271468000_bib26","doi-asserted-by":"crossref","first-page":"1141","DOI":"10.1084\/jem.20010916","article-title":"Changes in the proliferative activity of human hematopoietic stem cells in NOD\/SCID mice and enhancement of their transplantability after in vivo treatment with cell cycle inhibitors","volume":"196","author":"Cashman","year":"2002","journal-title":"J Exp Med"},{"key":"2022011315271468000_bib27","doi-asserted-by":"crossref","first-page":"893","DOI":"10.1182\/blood-2004-07-2859","article-title":"Efficient marking of human cells with rapid but transient repopulating activity in autografted recipients","volume":"106","author":"Glimm","year":"2005","journal-title":"Blood"},{"key":"2022011315271468000_bib28","doi-asserted-by":"crossref","first-page":"220","DOI":"10.1101\/gad.4.2.220","article-title":"Clonal and systemic analysis of long-term hematopoiesis in the mouse","volume":"4","author":"Jordan","year":"1990","journal-title":"Genes Dev"},{"key":"2022011315271468000_bib29","doi-asserted-by":"crossref","first-page":"2031","DOI":"10.1073\/pnas.92.6.2031","article-title":"Behavior of hematopoietic stem cells in a large animal","volume":"92","author":"Abkowitz","year":"1995","journal-title":"Proc Natl Acad Sci U S A"},{"key":"2022011315271468000_bib30","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1182\/blood-2004-04-1498","article-title":"Low-dose total body irradiation causes clonal fluctuation of primate hematopoietic stem and progenitor cells","volume":"105","author":"Laukkanen","year":"2005","journal-title":"Blood"},{"key":"2022011315271468000_bib31","doi-asserted-by":"crossref","first-page":"1273","DOI":"10.1182\/blood-2003-08-2935","article-title":"The impact of low-dose busulfan on clonal dynamics in nonhuman primates","volume":"104","author":"Kuramoto","year":"2004","journal-title":"Blood"},{"key":"2022011315271468000_bib32","doi-asserted-by":"crossref","first-page":"1225","DOI":"10.1038\/ni1393","article-title":"Individual stem cells with highly variable proliferation and self-renewal properties comprise the human hematopoietic stem cell compartment","volume":"7","author":"McKenzie","year":"2006","journal-title":"Nat Immunol"},{"key":"2022011315271468000_bib33","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1126\/science.283.5403.845","article-title":"Dependence of human stem cell engraftment and repopulation of NOD\/SCID mice on CXCR4","volume":"283","author":"Peled","year":"1999","journal-title":"Science"},{"key":"2022011315271468000_bib34","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/j.exphem.2006.04.002","article-title":"Mutual, reciprocal SDF-1\/CXCR4 interactions between hematopoietic and bone marrow stromal cells regulate human stem cell migration and development in NOD\/SCID chimeric mice","volume":"34","author":"Dar","year":"2006","journal-title":"Exp Hematol"},{"key":"2022011315271468000_bib35","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1182\/blood-2002-07-1995","article-title":"A highly sensitive strategy for SCID-repopulating cell assay by direct injection of primitive human hematopoietic cells into NOD\/SCID mice bone marrow","volume":"101","author":"Yahata","year":"2003","journal-title":"Blood"},{"key":"2022011315271468000_bib36","doi-asserted-by":"crossref","first-page":"3289","DOI":"10.1182\/blood.V95.11.3289","article-title":"The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: Role in transendothelial\/stromal migration and engraftment of NOD\/SCID mice","volume":"95","author":"Peled","year":"2000","journal-title":"Blood"},{"key":"2022011315271468000_bib37","doi-asserted-by":"crossref","first-page":"2456","DOI":"10.1172\/JCI188","article-title":"Mobilization and homing of peripheral blood progenitors is related to reversible downregulation of alpha4 beta1 integrin expression and function","volume":"101","author":"Prosper","year":"1998","journal-title":"J Clin Invest"}],"container-title":["Stem Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1634%2Fstemcells.2008-0552","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1634\/stemcells.2008-0552","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1634\/stemcells.2008-0552","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/26\/12\/3228\/41945088\/stmcls_26_12_3228.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/stmcls\/article-pdf\/26\/12\/3228\/41945088\/stmcls_26_12_3228.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,18]],"date-time":"2022-01-18T21:56:24Z","timestamp":1642542984000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/stmcls\/article\/26\/12\/3228-3236\/6402980"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2008,9,11]]},"references-count":37,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2008,9,11]]},"published-print":{"date-parts":[[2008,12,1]]}},"URL":"https:\/\/doi.org\/10.1634\/stemcells.2008-0552","relation":{"has-review":[{"id-type":"doi","id":"10.3410\/f.1148056.605168","asserted-by":"object"}]},"ISSN":["1066-5099","1549-4918"],"issn-type":[{"value":"1066-5099","type":"print"},{"value":"1549-4918","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2008,12,1]]},"published":{"date-parts":[[2008,9,11]]}}}