CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells

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 divisio...

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Published in:	Cell stem cell 2015-03, Vol.16 (3), p.302-313
Main Authors:	Laurenti, Elisa, Frelin, Catherine, Xie, Stephanie, Ferrari, Robin, Dunant, Cyrille F., Zandi, Sasan, Neumann, Andrea, Plumb, Ian, Doulatov, Sergei, Chen, Jing, April, Craig, Fan, Jian-Bing, Iscove, Norman, Dick, John E.
Format:	Article
Language:	eng
Subjects:	Cell Division - physiology Computer Simulation Cyclin-Dependent Kinase 6 - biosynthesis Gene Expression Regulation, Enzymologic - physiology Hematopoiesis - physiology Hematopoietic Stem Cells - cytology Hematopoietic Stem Cells - enzymology Humans Models, Biological
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Summary:	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. [Display omitted] •Human long-term (LT) and short-term (ST) HSCs are equally quiescent•LT- and ST-HSCs differ in division kinetics and expression of CDK6•CDK6 expression regulates the timing of exit from quiescence•Differential regulation of quiescence helps maintain hematopoiesis The hematopoietic stem cell (HSC) compartment is heterogeneous in terms of cell cycle properties. Laurenti et al. show that the timing of exit from quiescence in human HSC subsets is controlled by CDK6 expression levels. This differential control has an impact on the long-term preservation of the HSC pool.
ISSN:	1934-5909 1875-9777