biostudies-literature00540Umemoto TFriends of Leukemia Research FundShinnihon Foundation of Advanced Medical Treatment ResearchNational Medical Research CouncilIchiro Kanehara FoundationJapan Society for the Promotion of Science2097-2113https://www.ebi.ac.uk/biostudies/studies/S-EPMC6080917biostudies-literatureUnknown215(8)Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (ΔΨ_m). 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 ΔΨ_m as a result of increased intracellular Ca²⁺ level. Although further activation of Ca²⁺-mitochondria 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⁺-mitochondria pathway induces HSC division critically to determine HSC cell fate.The Journal of experimental medicineCa²⁺-mitochondria axis drives cell division in hematopoietic stem cells.PMC6080917NMRC/STaR/0019/201417K1619026221309Suda THashimoto MNakamura-Ishizu AMatsumura TUmemoto T54falseCa²⁺-mitochondria axis drives cell division in hematopoietic stem cells.Most of the hematopoietic stem cells (HSCs) within the bone marrow (BM) show quiescent state with a low mitochondrial membrane potential (ΔΨ_m). 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 ΔΨ_m as a result of increased intracellular Ca²⁺ level. Although further activation of Ca²⁺-mitochondria 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⁺-mitochondria pathway induces HSC division critically to determine HSC cell fate.2018-01-01T00:00:00Z2018 Aug2024-10-15T15:52:24.16Z2019-03-26T22:50:15ZS-EPMC60809172994600010.1084/jem.20180421