{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T14:06:28Z","timestamp":1792073188948,"version":"4.4.0"},"reference-count":47,"publisher":"Rockefeller University Press","issue":"8","license":[{"start":{"date-parts":[[2018,6,26]],"date-time":"2018-06-26T00:00:00Z","timestamp":1529971200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.rupress.org\/terms\/"},{"start":{"date-parts":[[2019,2,3]],"date-time":"2019-02-03T00:00:00Z","timestamp":1549152000000},"content-version":"vor","delay-in-days":222,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-sa\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001349","name":"National Medical Research Council","doi-asserted-by":"publisher","award":["NMRC\/STaR\/0019\/2014"],"award-info":[{"award-number":["NMRC\/STaR\/0019\/2014"]}],"id":[{"id":"10.13039\/501100001349","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["17K16190"],"award-info":[{"award-number":["17K16190"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001691","name":"Japan Society for the Promotion of Science","doi-asserted-by":"publisher","award":["26221309"],"award-info":[{"award-number":["26221309"]}],"id":[{"id":"10.13039\/501100001691","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003837","name":"Ichiro Kanehara Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100003837","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017102","name":"Friends of Leukemia Research Fund","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017102","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100018289","name":"Shinnihon Foundation of Advanced Medical Treatment Research","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100018289","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["rupress.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2018,8,6]]},"abstract":"<jats:p>Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (\u0394\u03a8m). In contrast, upon stress hematopoiesis, HSCs actively start to divide. However, the underlying mechanism for the initiation of HSC division still remains unclear. To elucidate the mechanism underlying the transition of cell cycle state in HSCs, we analyzed the change of mitochondria in HSCs after BM suppression induced by 5-fluoruracil (5-FU). We found that HSCs initiate cell division after exhibiting enhanced \u0394\u03a8m as a result of increased intracellular Ca2+ level. Although further activation of Ca2+\u2013mitochondria pathway led to loss of HSCs after cell division, the appropriate suppression of intracellular Ca2+ level by exogenous adenosine or Nifedipine, a Ca2+ channel blocker, prolonged cell division interval in HSCs, and simultaneously achieved both cell division and HSC maintenance. Collectively, our results indicate that the Ca2+\u2013mitochondria pathway induces HSC division critically to determine HSC cell fate.<\/jats:p>","DOI":"10.1084\/jem.20180421","type":"journal-article","created":{"date-parts":[[2018,6,26]],"date-time":"2018-06-26T10:23:28Z","timestamp":1530008608000},"page":"2097-2113","update-policy":"https:\/\/doi.org\/10.1084\/jem.crossmarkpolicy","source":"Crossref","is-referenced-by-count":148,"title":["Ca2+\u2013mitochondria axis drives cell division in hematopoietic stem cells"],"prefix":"10.1084","volume":"215","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-0423-9003","authenticated-orcid":true,"given":"Terumasa","family":"Umemoto","sequence":"first","affiliation":[{"name":"International Research Center for Medical Sciences, Kumamoto University, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Hashimoto","sequence":"additional","affiliation":[{"name":"International Research Center for Medical Sciences, Kumamoto University, Japan 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takayoshi","family":"Matsumura","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ayako","family":"Nakamura-Ishizu","sequence":"additional","affiliation":[{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7540-1771","authenticated-orcid":true,"given":"Toshio","family":"Suda","sequence":"additional","affiliation":[{"name":"International Research Center for Medical Sciences, Kumamoto University, Japan 1"},{"name":"Cancer Science Institute of Singapore, National University of Singapore, Singapore 2"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2018,6,26]]},"reference":[{"key":"2023072604194856800_bib1","doi-asserted-by":"publisher","first-page":"1878","DOI":"10.1002\/stem.1711","article-title":"Critical role of Jak2 in the maintenance and function of adult hematopoietic stem cells","volume":"32","author":"Akada","year":"2014","journal-title":"Stem Cells."},{"key":"2023072604194856800_bib2","doi-asserted-by":"publisher","first-page":"1653","DOI":"10.1093\/bioinformatics\/btr261","article-title":"DREME: motif discovery in transcription factor ChIP-seq data","volume":"27","author":"Bailey","year":"2011","journal-title":"Bioinformatics."},{"key":"2023072604194856800_bib3","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1038\/nature09135","article-title":"Quiescent haematopoietic stem cells are activated by IFN-gamma in response to chronic infection","volume":"465","author":"Baldridge","year":"2010","journal-title":"Nature."},{"key":"2023072604194856800_bib4","doi-asserted-by":"publisher","first-page":"E3345","DOI":"10.1073\/pnas.1423357112","article-title":"Epidermal TRPM8 channel isoform controls the balance between keratinocyte proliferation and differentiation in a cold-dependent manner","volume":"112","author":"Bidaux","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604194856800_bib5","doi-asserted-by":"publisher","first-page":"223","DOI":"10.1038\/nature16943","article-title":"Hoxb5 marks long-term haematopoietic stem cells and reveals a homogenous perivascular niche","volume":"530","author":"Chen","year":"2016","journal-title":"Nature."},{"key":"2023072604194856800_bib6","doi-asserted-by":"publisher","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":"2023072604194856800_bib7","doi-asserted-by":"publisher","first-page":"3159","DOI":"10.1172\/JCI61636","article-title":"Purinergic P2Y14 receptor modulates stress-induced hematopoietic stem\/progenitor cell senescence","volume":"124","author":"Cho","year":"2014","journal-title":"J. Clin. Invest."},{"key":"2023072604194856800_bib8","doi-asserted-by":"publisher","first-page":"904","DOI":"10.1038\/nature07815","article-title":"IFNalpha activates dormant haematopoietic stem cells in vivo","volume":"458","author":"Essers","year":"2009","journal-title":"Nature."},{"key":"2023072604194856800_bib9","doi-asserted-by":"publisher","first-page":"e69718","DOI":"10.1371\/journal.pone.0069718","article-title":"Selective inhibition by ethanol of mitochondrial calcium influx mediated by uncoupling protein-2 in relation to N-methyl-d-aspartate cytotoxicity in cultured neurons","volume":"8","author":"Fukumori","year":"2013","journal-title":"PLoS One."},{"key":"2023072604194856800_bib10","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1084\/jem.20130428","article-title":"Fgd5 identifies hematopoietic stem cells in the murine bone marrow","volume":"211","author":"Gazit","year":"2014","journal-title":"J. Exp. Med."},{"key":"2023072604194856800_bib11","doi-asserted-by":"publisher","first-page":"R24","DOI":"10.1186\/gb-2007-8-2-r24","article-title":"Quantifying similarity between motifs","volume":"8","author":"Gupta","year":"2007","journal-title":"Genome Biol."},{"key":"2023072604194856800_bib12","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1016\/0092-8674(95)90430-1","article-title":"Decoding of cytosolic calcium oscillations in the mitochondria","volume":"82","author":"Hajn\u00f3czky","year":"1995","journal-title":"Cell."},{"key":"2023072604194856800_bib13","doi-asserted-by":"crossref","first-page":"113","DOI":"10.3389\/fendo.2012.00113","article-title":"An emerging role for adenosine and its receptors in bone homeostasis","volume":"3","author":"Ham","year":"2012","journal-title":"Front. Endocrinol. (Lausanne)."},{"key":"2023072604194856800_bib14","doi-asserted-by":"crossref","first-page":"1237","DOI":"10.1182\/blood.V78.5.1237.1237","article-title":"Most primitive hematopoietic stem cells are stimulated to cycle rapidly after treatment with 5-fluorouracil","volume":"78","author":"Harrison","year":"1991","journal-title":"Blood."},{"key":"2023072604194856800_bib15","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1083\/jcb.201004152","article-title":"S-glutathionylation activates STIM1 and alters mitochondrial homeostasis","volume":"190","author":"Hawkins","year":"2010","journal-title":"J. Cell Biol."},{"key":"2023072604194856800_bib16","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1038\/s41467-018-02866-0","article-title":"Single-cell full-length total RNA sequencing uncovers dynamics of recursive splicing and enhancer RNAs","volume":"9","author":"Hayashi","year":"2018","journal-title":"Nat. Commun."},{"key":"2023072604194856800_bib17","doi-asserted-by":"publisher","first-page":"3521","DOI":"10.1182\/blood-2009-12-253989","article-title":"Hoxb4-YFP reporter mouse model: a novel tool for tracking HSC development and studying the role of Hoxb4 in hematopoiesis","volume":"117","author":"Hills","year":"2011","journal-title":"Blood."},{"key":"2023072604194856800_bib18","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1016\/j.stem.2018.01.017","article-title":"CD150high Bone Marrow Tregs Maintain Hematopoietic Stem Cell Quiescence and Immune Privilege via Adenosine","volume":"22","author":"Hirata","year":"2018","journal-title":"Cell Stem Cell."},{"key":"2023072604194856800_bib19","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1038\/nrm3772","article-title":"Metabolic requirements for the maintenance of self-renewing stem cells","volume":"15","author":"Ito","year":"2014","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2023072604194856800_bib20","doi-asserted-by":"publisher","first-page":"1590","DOI":"10.1182\/blood-2005-03-0860","article-title":"Distinctive and indispensable roles of PU.1 in maintenance of hematopoietic stem cells and their differentiation","volume":"106","author":"Iwasaki","year":"2005","journal-title":"Blood."},{"key":"2023072604194856800_bib21","doi-asserted-by":"publisher","first-page":"3697","DOI":"10.1007\/s00018-017-2545-6","article-title":"ATP-induced Ca2+-signalling mechanisms in the regulation of mesenchymal stem cell migration","volume":"74","author":"Jiang","year":"2017","journal-title":"Cell. Mol. Life Sci."},{"key":"2023072604194856800_bib22","doi-asserted-by":"publisher","first-page":"13807","DOI":"10.1073\/pnas.96.24.13807","article-title":"Regulation of mitochondrial ATP synthesis by calcium: evidence for a long-term metabolic priming","volume":"96","author":"Jouaville","year":"1999","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604194856800_bib23","doi-asserted-by":"publisher","first-page":"2403","DOI":"10.1084\/jem.20110447","article-title":"Evi1 is essential for hematopoietic stem cell self-renewal, and its expression marks hematopoietic cells with long-term multilineage repopulating activity","volume":"208","author":"Kataoka","year":"2011","journal-title":"J. Exp. Med."},{"key":"2023072604194856800_bib24","doi-asserted-by":"publisher","first-page":"6342","DOI":"10.1182\/blood-2008-12-192054","article-title":"Prospective isolation and molecular characterization of hematopoietic stem cells with durable self-renewal potential","volume":"113","author":"Kent","year":"2009","journal-title":"Blood."},{"key":"2023072604194856800_bib25","doi-asserted-by":"publisher","first-page":"360","DOI":"10.1038\/nature02246","article-title":"The mitochondrial calcium uniporter is a highly selective ion channel","volume":"427","author":"Kirichok","year":"2004","journal-title":"Nature."},{"key":"2023072604194856800_bib26","doi-asserted-by":"publisher","first-page":"4383","DOI":"10.1182\/blood-2009-07-230292","article-title":"Necdin restricts proliferation of hematopoietic stem cells during hematopoietic regeneration","volume":"114","author":"Kubota","year":"2009","journal-title":"Blood."},{"key":"2023072604194856800_bib27","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1016\/j.stem.2008.11.006","article-title":"p53 regulates hematopoietic stem cell quiescence","volume":"4","author":"Liu","year":"2009","journal-title":"Cell Stem Cell."},{"key":"2023072604194856800_bib28","doi-asserted-by":"publisher","first-page":"1553","DOI":"10.1016\/j.cell.2015.04.054","article-title":"Enhancing Hematopoietic Stem Cell Transplantation Efficacy by Mitigating Oxygen Shock","volume":"161","author":"Mantel","year":"2015","journal-title":"Cell."},{"key":"2023072604194856800_bib29","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/nm.3647","article-title":"Hematopoietic stem cell niche maintenance during homeostasis and regeneration","volume":"20","author":"Mendelson","year":"2014","journal-title":"Nat. Med."},{"key":"2023072604194856800_bib30","doi-asserted-by":"publisher","first-page":"380","DOI":"10.1016\/j.stem.2008.01.015","article-title":"The transcription factor EGR1 controls both the proliferation and localization of hematopoietic stem cells","volume":"2","author":"Min","year":"2008","journal-title":"Cell Stem Cell."},{"key":"2023072604194856800_bib31","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1016\/j.stem.2007.02.001","article-title":"Foxo3a is essential for maintenance of the hematopoietic stem cell pool","volume":"1","author":"Miyamoto","year":"2007","journal-title":"Cell Stem Cell."},{"key":"2023072604194856800_bib32","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1084\/jem.20131043","article-title":"Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons","volume":"211","author":"Pietras","year":"2014","journal-title":"J. Exp. Med."},{"key":"2023072604194856800_bib33","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1016\/S0031-6997(24)01373-5","article-title":"Receptors for purines and pyrimidines","volume":"50","author":"Ralevic","year":"1998","journal-title":"Pharmacol. Rev."},{"key":"2023072604194856800_bib34","doi-asserted-by":"publisher","first-page":"3207","DOI":"10.1038\/onc.2011.35","article-title":"The pro-longevity gene FoxO3 is a direct target of the p53 tumor suppressor","volume":"30","author":"Renault","year":"2011","journal-title":"Oncogene."},{"key":"2023072604194856800_bib35","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1016\/j.immuni.2016.08.007","article-title":"Hematopoietic Stem Cells Are the Major Source of Multilineage Hematopoiesis in Adult Animals","volume":"45","author":"Sawai","year":"2016","journal-title":"Immunity."},{"key":"2023072604194856800_bib36","doi-asserted-by":"publisher","first-page":"351","DOI":"10.1152\/jn.00010.2001","article-title":"A2 adenosine receptors inhibit calcium influx through L-type calcium channels in rod photoreceptors of the salamander retina","volume":"87","author":"Stella","year":"2002","journal-title":"J. Neurophysiol."},{"key":"2023072604194856800_bib37","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","article-title":"Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles","volume":"102","author":"Subramanian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA."},{"key":"2023072604194856800_bib38","doi-asserted-by":"publisher","first-page":"298","DOI":"10.1016\/j.stem.2011.09.010","article-title":"Metabolic regulation of hematopoietic stem cells in the hypoxic niche","volume":"9","author":"Suda","year":"2011","journal-title":"Cell Stem Cell."},{"key":"2023072604194856800_bib39","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1016\/S0301-0082(99)00011-8","article-title":"Distribution, biochemistry and function of striatal adenosine A2A receptors","volume":"59","author":"Svenningsson","year":"1999","journal-title":"Prog. Neurobiol."},{"key":"2023072604194856800_bib40","doi-asserted-by":"publisher","first-page":"391","DOI":"10.1016\/j.stem.2010.06.020","article-title":"Regulation of the HIF-1alpha level is essential for hematopoietic stem cells","volume":"7","author":"Takubo","year":"2010","journal-title":"Cell Stem Cell."},{"key":"2023072604194856800_bib41","doi-asserted-by":"publisher","first-page":"e39722","DOI":"10.1371\/journal.pone.0039722","article-title":"The mitochondrial Ca2+ uniporter MCU is essential for glucose-induced ATP increases in pancreatic \u03b2-cells","volume":"7","author":"Tarasov","year":"2012","journal-title":"PLoS One."},{"key":"2023072604194856800_bib42","doi-asserted-by":"publisher","first-page":"7733","DOI":"10.4049\/jimmunol.177.11.7733","article-title":"Expression of Integrin beta3 is correlated to the properties of quiescent hemopoietic stem cells possessing the side population phenotype","volume":"177","author":"Umemoto","year":"2006","journal-title":"J. Immunol."},{"key":"2023072604194856800_bib43","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1182\/blood-2011-02-335430","article-title":"Integrin-\u03b1v\u03b23 regulates thrombopoietin-mediated maintenance of hematopoietic stem cells","volume":"119","author":"Umemoto","year":"2012","journal-title":"Blood."},{"key":"2023072604194856800_bib44","doi-asserted-by":"publisher","first-page":"2390","DOI":"10.15252\/embj.201796771","article-title":"Integrin \u03b1v\u03b23 enhances the suppressive effect of interferon-\u03b3 on hematopoietic stem cells","volume":"36","author":"Umemoto","year":"2017","journal-title":"EMBO J."},{"key":"2023072604194856800_bib45","doi-asserted-by":"publisher","first-page":"13125","DOI":"10.1038\/ncomms13125","article-title":"Specification of haematopoietic stem cell fate via modulation of mitochondrial activity","volume":"7","author":"Vannini","year":"2016","journal-title":"Nat. Commun."},{"key":"2023072604194856800_bib46","doi-asserted-by":"publisher","first-page":"4116","DOI":"10.1038\/sj.emboj.7600419","article-title":"Transcription factor Gfi1 regulates self-renewal and engraftment of hematopoietic stem cells","volume":"23","author":"Zeng","year":"2004","journal-title":"EMBO J."},{"key":"2023072604194856800_bib47","doi-asserted-by":"publisher","first-page":"4314","DOI":"10.1182\/blood-2004-11-4418","article-title":"Murine hematopoietic stem cells change their surface phenotype during ex vivo expansion","volume":"105","author":"Zhang","year":"2005","journal-title":"Blood."}],"container-title":["Journal of Experimental Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/215\/8\/2097\/1759606\/jem_20180421.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/rupress.org\/jem\/article-pdf\/215\/8\/2097\/1759606\/jem_20180421.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,5]],"date-time":"2025-07-05T06:12:49Z","timestamp":1751695969000},"score":1,"resource":{"primary":{"URL":"https:\/\/rupress.org\/jem\/article\/215\/8\/2097\/46039\/Ca2-mitochondria-axis-drives-cell-division-in"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,26]]},"references-count":47,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2018,8,6]]}},"URL":"https:\/\/doi.org\/10.1084\/jem.20180421","relation":{},"ISSN":["0022-1007","1540-9538"],"issn-type":[{"value":"0022-1007","type":"print"},{"value":"1540-9538","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,26]]}}}