Ca(2+)–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 Ca(2+) level. Although further activation of Ca(2+)–mitochondria pathway led to loss of HSCs after cell division, the appropriate suppression of intracellular Ca(2+) level by exogenous adenosine or Nifedipine, a Ca(2+) channel blocker, prolonged cell division interval in HSCs, and simultaneously achieved both cell division and HSC maintenance. Collectively, our results indicate that the Ca(2+)–mitochondria pathway induces HSC division critically to determine HSC cell fate.