期刊
CELL STEM CELL
卷 16, 期 3, 页码 302-313出版社
CELL PRESS
DOI: 10.1016/j.stem.2015.01.017
关键词
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资金
- Swiss National Science Foundation
- Roche
- Fondation Suisse pour les Bourses en Medecine et Biologie
- Swedish Research Council
- Canadian Institutes of Health Research (CIHR)
- Aplastic Anemia and Myelodysplasia Association of Canada
- CIHR
- Canadian Cancer Society
- Terry Fox Foundation
- Genome Canada through Ontario Genomics Institute
- Ontario Institute for Cancer Research
- province of Ontario, a Canada Research Chair
- Princess Margaret Hospital foundation
- Ontario Ministry of Health and Long Term Care (OMOHLTC)
- Wellcome Trust
- MRC
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.
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