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      CDK6 Levels Regulate Quiescence Exit in Human Hematopoietic Stem Cells

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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.

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          Highlights

          • 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

          Abstract

          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.

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          Most cited references 34

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          Global analysis of proliferation and cell cycle gene expression in the regulation of hematopoietic stem and progenitor cell fates

          Knowledge of the molecular networks controlling the proliferation and fate of hematopoietic stem cells (HSC) is essential to understand their function in maintaining blood cell production during normal hematopoiesis and upon clinical transplantation. Using highly purified stem and progenitor cell populations, we define the proliferation index and status of the cell cycle machinery at discrete stages of hematopoietic differentiation and during cytokine-mediated HSC mobilization. We identify distinct sets of cell cycle proteins that specifically associate with differentiation, self-renewal, and maintenance of quiescence in HSC and progenitor cells. Moreover, we describe a striking inequality of function among in vivo cycling and quiescent HSC by demonstrating that their long-term engraftment potential resides predominantly in the G0 fraction. These data provide a direct link between HSC proliferation and function and identify discrete molecular targets in regulating HSC cell fate decisions that could have implications for both the therapeutic use of HSC and the understanding of leukemic transformation.
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            The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype.

            The Thy-1.1loSca-1hiLin-/lo population, representing 0.05% of C57BL/Ka-Thy-1.1 bone marrow, is highly enriched for hematopoietic stem cells and includes all multipotent progenitors in this mouse strain; however, the functional reconstituting activity of this fraction is heterogeneous. Only around 25% of clonal reconstitutions by cells from this population are long term; remaining clones yield transient multilineage reconstitutions. By fractionating based on lineage marker expression, the Thy-1.1loSca-1hiLin-/lo population has been resolved into three subpopulations: Lin-Mac-1-CD4-; Lin-Mac-1loCD4-; and Mac-1loCD4lo. Of these, only the Lin-Mac-1-CD4- population is highly enriched for long-term reconstituting hematopoietic stem cells. A comparison of transient and long-term multipotent progenitors indicates that long-term progenitors have less CFU-S activity, are equally radioprotective, and are less frequently in cell cycle. The ability to predict the longevity of reconstitution based on lineage marker expression indicates that reconstitution potential is deterministic, not stochastic.
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              In vivo proliferation and cell cycle kinetics of long-term self-renewing hematopoietic stem cells.

              A rare set of hematopoietic stem cells (HSC) must undergo a massive expansion to produce mature blood cells. The phenotypic isolation of HSC from mice offers the opportunity to determine directly their proliferation kinetics. We analyzed the proliferation and cell cycle kinetics of long-term self-renewing HSC (LT-HSC) in normal adult mice. At any one time, approximately 5% of LT-HSC were in S/G2/M phases of the cell cycle and another 20% were in G1 phase. BrdUrd incorporation was used to determine the rate at which different cohorts of HSC entered the cell cycle over time. About 50% of LT-HSC incorporated BrdUrd by 6 days and >90% incorporated BrdUrd by 30 days. By 6 months, 99% of LT-HSC had incorporated BrdUrd. We calculated that approximately 8% of LT-HSC asynchronously entered the cell cycle per day. Nested reverse transcription-PCR analysis revealed cyclin D2 expression in a high proportion of LT-HSC. Although approximately 75% of LT-HSC are quiescent in G0 at any one time, all HSC are recruited into cycle regularly such that 99% of LT-HSC divide on average every 57 days.
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                Author and article information

                Contributors
                Journal
                Cell Stem Cell
                Cell Stem Cell
                Cell Stem Cell
                Cell Press
                1934-5909
                1875-9777
                05 March 2015
                05 March 2015
                : 16
                : 3
                : 302-313
                Affiliations
                [1 ]Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
                [2 ]Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada
                [3 ]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 ]Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
                Author notes
                []Corresponding author el422@ 123456cam.ac.uk
                [∗∗ ]Corresponding author jdick@ 123456uhnresearch.ca
                [8]

                Co-first author

                [9]

                Present address: Wellcome Trust – Medical Research Council Cambridge Stem Cell Institute, Department of Haematology, University of Cambridge, Cambridge, CB2 0AH, UK

                Article
                S1934-5909(15)00018-1
                10.1016/j.stem.2015.01.017
                4359055
                25704240
                © 2015 The Authors

                This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

                Categories
                Article

                Molecular medicine

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