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      CDK6 levels regulate quiescence exit in human hematopoietic stem cells.

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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.

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

          Emmanuelle Passegué, Amy J. Wagers, Sylvie Giuriato … (2005)
          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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            Defining Hematopoietic Stem and Progenitor Cell Turnover by Analysis of Histone 2B-GFP Dilution

            Adlen Foudi, Konrad Hochedlinger, Denille Van Buren … (2008)
            Hematopoietic stem cells (HSCs) are thought to divide infrequently based on their resistance to cytotoxic injury targeted at rapidly cycling cells1, 2 and have been presumed to retain labels such as the nucleotide analogue 5-bromodeoxyuridine (BrdU). However, recently it has been demonstrated that BrdU-retention is neither sensitive nor specific for HSCs3. Here we show that transient, transgenic expression of a Histone2B (H2B)-Green Fluorescent Protein (GFP) fusion protein in mice allows superior labeling of HSCs and permits improved analysis of their turnover in combination with other markers. Mathematical modeling of H2B-GFP dilution in HSCs, identified with a highly stringent marker combination (L−K+S+CD48−CD150+)4, revealed unexpected heterogeneity in their proliferation rates and suggests that ~ 20% of HSCs turn over at an extremely low rate (≤ 0.8–1.8% per day). Prospective isolation and transplantation of L−K+S+CD48−CD150+ HSCs with different H2B-GFP levels revealed that higher H2B-GFP label retention correlates with superior long-term repopulation potential.
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              The long-term repopulating subset of hematopoietic stem cells is deterministic and isolatable by phenotype.

              Sean Morrison, Irving L Weissman (1994)
              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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                Author and article information

                Journal
                Journal ID (iso-abbrev): Cell Stem Cell
                Title: Cell stem cell
                Publisher: Elsevier BV
                ISSN (Electronic): 1875-9777
                ISSN (Print): 1875-9777
                Publication date (Electronic): Mar 05 2015
                Volume: 16
                Issue: 3
                Affiliations
                [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.
                Article
                Publisher Item ID: S1934-5909(15)00018-1
                DOI: 10.1016/j.stem.2015.01.017
                PMC ID: 4359055
                PubMed ID: 25704240
                SO-VID: 354a941e-28f2-45bd-a457-d40cf9b2c693
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