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Cell Stem Cell. 2015 Mar 5;16(3):302-13. doi: 10.1016/j.stem.2015.01.017. Epub 2015 Feb 19.

CDK6 levels regulate quiescence exit in human hematopoietic stem cells.

Author information

1
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada. Electronic address: el422@cam.ac.uk.
2
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
3
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Ecole Normale Supérieure de Cachan, Département de Biologie, Cachan, 94235, France.
4
Ecole Polytechnique Fédérale de Lausanne, LMC, Station 12, Lausanne, CH-1015, Switzerland.
5
Division of Pediatric Hematology/Oncology, Boston Children's Hospital and Harvard Medical School, Harvard Stem Cell Institute, Boston, MA 02115, USA.
6
Illumina, San Diego, CA 92121, USA.
7
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada.
8
Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: jdick@uhnresearch.ca.

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.

PMID:
25704240
PMCID:
PMC4359055
DOI:
10.1016/j.stem.2015.01.017
[Indexed for MEDLINE]
Free PMC Article

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