CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells
Dick, John E
Cell Stem Cell
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Laurenti, E., Frelin, C., Xie, S., Ferrari, R., Dunant, C., Zandi, S., Neumann, A., et al. (2015). CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells. Cell Stem Cell, 16 302-313. https://doi.org/10.1016/j.stem.2015.01.017
Regulated blood production is achieved through the hierarchical organization of dormant hematopoietic stem cell (HSC) subsets that differ in self-renewal potential and division frequency, with long-term (LT)-HSCs dividing the least. The molecular mechanisms underlying this variability in HSC division kinetics are unknown. We report here that quiescence exit kinetics are differentially regulated within human HSC subsets through the expression level of CDK6. LT-HSCs lack CDK6 protein. Short-term (ST)-HSCs are also quiescent but contain high CDK6 protein levels that permit rapid cell cycle entry upon mitogenic stimulation. Enforced CDK6 expression in LT-HSCs shortens quiescence exit and confers competitive advantage without impacting function. Computational modeling suggests that this independent control of quiescence exit kinetics inherently limits LT-HSC divisions and preserves the HSC pool to ensure lifelong hematopoiesis. Thus, differential expression of CDK6 underlies heterogeneity in stem cell quiescence states that functionally regulates this highly regenerative system.
This work was supported by the Swiss National Science Foundation (E.L.), Roche (E.L.), the Fondation Suisse pour les Bourses en Me´ decine et Biologie (E.L.), the Swedish Research Council (S.Z.); and a Canadian Institutes of Health Research (CIHR) fellowship in partnership with the Aplastic Anemia and Myelodysplasia Association of Canada (S.Z.). Work in J.E.D.’s laboratory is supported by grants from the CIHR, Canadian Cancer Society, Terry Fox Foundation, Genome Canada through the Ontario Genomics Institute, Ontario Institute for Cancer Research with funds from the province of Ontario, a Canada Research Chair, the Princess Margaret Hospital foundation, and the Ontario Ministry of Health and Long Term Care (OMOHLTC). Research in E.L.’s laboratory is currently supported by a recruitment support from the Wellcome Trust and a core support grant from the Wellcome Trust and MRC to the Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute.
External DOI: https://doi.org/10.1016/j.stem.2015.01.017
This record's URL: https://www.repository.cam.ac.uk/handle/1810/247475
Attribution 2.0 UK: England & Wales
Licence URL: http://creativecommons.org/licenses/by/2.0/uk/
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