CUED Publications database

CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells

Laurenti, E and Frelin, C and Xie, S and Ferrari, R and Dunant, C and Zandi, S and Neumann, A and Plumb, I and Doulatov, S and Chen, J and April, C and Fan, J-B and Iscove, N and Dick, J (2015) CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells. Cell Stem Cell. ISSN 1934-5909

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Abstract

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. The hematopoietic stem cell (HSC) compartment is heterogeneous in terms of cell cycle properties. Laurenti etal. 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.

Item Type: Article
Uncontrolled Keywords: StemCellInstitute
Subjects: UNSPECIFIED
Divisions: Div D > Structures
Depositing User: Cron Job
Date Deposited: 17 Jul 2017 18:57
Last Modified: 21 Sep 2017 01:36
DOI: