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      Clonal dynamics of native haematopoiesis.

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          Abstract

          It is currently thought that life-long blood cell production is driven by the action of a small number of multipotent haematopoietic stem cells. Evidence supporting this view has been largely acquired through the use of functional assays involving transplantation. However, whether these mechanisms also govern native non-transplant haematopoiesis is entirely unclear. Here we have established a novel experimental model in mice where cells can be uniquely and genetically labelled in situ to address this question. Using this approach, we have performed longitudinal analyses of clonal dynamics in adult mice that reveal unprecedented features of native haematopoiesis. In contrast to what occurs following transplantation, steady-state blood production is maintained by the successive recruitment of thousands of clones, each with a minimal contribution to mature progeny. Our results demonstrate that a large number of long-lived progenitors, rather than classically defined haematopoietic stem cells, are the main drivers of steady-state haematopoiesis during most of adulthood. Our results also have implications for understanding the cellular origin of haematopoietic disease.

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          Most cited references20

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          Lineage tracing.

          Lineage tracing is the identification of all progeny of a single cell. Although its origins date back to developmental biology of invertebrates in the 19(th) century, lineage tracing is now an essential tool for studying stem cell properties in adult mammalian tissues. Lineage tracing provides a powerful means of understanding tissue development, homeostasis, and disease, especially when it is combined with experimental manipulation of signals regulating cell-fate decisions. Recently, the combination of inducible recombinases, multicolor reporter constructs, and live-cell imaging has provided unprecedented insights into stem cell biology. Here we discuss the different experimental strategies currently available for lineage tracing, their associated caveats, and new opportunities to integrate lineage tracing with the monitoring of intracellular signaling pathways. Copyright © 2012 Elsevier Inc. All rights reserved.
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            Efficient method to generate single-copy transgenic mice by site-specific integration in embryonic stem cells.

            Transgenic and gene-targeted mutant mice provide powerful tools for analysis of the cellular processes involved in early development and in the pathogenesis of many diseases. Here we describe a transgene integration strategy mediated by site-specific recombination that allows establishment of multiple embryonic stem (ES) cell lines carrying tetracycline-inducible genes targeted to a specific locus to assure predictable temporal and spatial expression in ES cells and mice. Using homologous recombination we inserted an frt homing site into which tetracycline-inducible transgenes can be integrated efficiently in the presence of FLPe recombinase. This strategy and the vectors described here are generally applicable to any locus in ES cells and should allow for the rapid production of mice with transgenes efficiently targeted to a defined site. (c) 2006 Wiley-Liss, Inc.
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              Defining Hematopoietic Stem and Progenitor Cell Turnover by Analysis of Histone 2B-GFP Dilution

              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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                Author and article information

                Journal
                Nature
                Nature
                1476-4687
                0028-0836
                Oct 16 2014
                : 514
                : 7522
                Affiliations
                [1 ] 1] Stem Cell Program, Children's Hospital, Boston, Massachusetts 02115, USA [2] Department of Stem Cell and Regenerative Biology, Harvard University, Cambridge, Massachusetts 02138, USA [3] Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
                [2 ] Stem Cell Program, Children's Hospital, Boston, Massachusetts 02115, USA.
                [3 ] Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
                [4 ] Department of Immunology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
                [5 ] Watson School of Biological Sciences, Cold Spring Harbor Laboratory, Cold Spring Harbor, New York 11724, USA.
                [6 ] Department of Systems Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
                Article
                nature13824 NIHMS678975
                10.1038/nature13824
                25296256
                4f291380-1c41-400d-bb2d-9d657ead95b4
                History

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