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      Use of Imaging Techniques to Illuminate Dynamics of Hematopoietic Stem Cells and Their Niches

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          Continuous generation of blood cells over an organism's lifetime is supported by hematopoietic stem/progenitor cells (HSPCs) capable of producing all hematopoietic cell subtypes. Adult mammalian HSPCs are localized to bone marrow and regulated by their neighboring microenvironment, or “niche.” Because interactions of HSPCs with their niches are highly dynamic and complex, the recent development of imaging technologies provides a powerful new tool to understand stem cell/niche biology. In this review, we discuss recent advances in our understanding of dynamic HSPC/niche interactions during development, homeostasis, disease states or aging with a focus on studies advanced by imaging analysis. We also summarize methods to visualize HSPCs and niche cells in vivo, including use of HSPC reporter mice and chemical probes. Findings emerging from these investigations could suggest novel therapies for diseases and aging.

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          Most cited references 78

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          Animal models of human disease: zebrafish swim into view.

          Despite the pre-eminence of the mouse in modelling human disease, several aspects of murine biology limit its routine use in large-scale genetic and therapeutic screening. Many researchers who are interested in an embryologically and genetically tractable disease model have now turned to zebrafish. Zebrafish biology allows ready access to all developmental stages, and the optical clarity of embryos and larvae allow real-time imaging of developing pathologies. Sophisticated mutagenesis and screening strategies on a large scale, and with an economy that is not possible in other vertebrate systems, have generated zebrafish models of a wide variety of human diseases. This Review surveys the achievements and potential of zebrafish for modelling human diseases and for drug discovery and development.
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            Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.

            Bone marrow hematopoietic stem cells (HSCs) are crucial to maintain lifelong production of all blood cells. Although HSCs divide infrequently, it is thought that the entire HSC pool turns over every few weeks, suggesting that HSCs regularly enter and exit cell cycle. Here, we combine flow cytometry with label-retaining assays (BrdU and histone H2B-GFP) to identify a population of dormant mouse HSCs (d-HSCs) within the lin(-)Sca1+cKit+CD150+CD48(-)CD34(-) population. Computational modeling suggests that d-HSCs divide about every 145 days, or five times per lifetime. d-HSCs harbor the vast majority of multilineage long-term self-renewal activity. While they form a silent reservoir of the most potent HSCs during homeostasis, they are efficiently activated to self-renew in response to bone marrow injury or G-CSF stimulation. After re-establishment of homeostasis, activated HSCs return to dormancy, suggesting that HSCs are not stochastically entering the cell cycle but reversibly switch from dormancy to self-renewal under conditions of hematopoietic stress.
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              Endothelial and perivascular cells maintain haematopoietic stem cells

              Multiple cell types have been proposed to create niches for haematopoietic stem cells (HSCs). However, the expression patterns of HSC maintenance factors have not been systematically studied and no such factor has been conditionally deleted from any candidate niche cell. Thus, the cellular sources of these factors are undetermined. Stem Cell Factor (SCF) is a key niche component that maintains HSCs. Using Scfgfp knock-in mice we found Scf was primarily expressed by perivascular cells throughout bone marrow. HSC frequency and function were not affected when Scf was conditionally deleted from haematopoietic cells, osteoblasts, Nestin-Cre, or Nestin-CreER-expressing cells. However, HSCs were depleted from bone marrow when Scf was deleted from endothelial cells or Leptin receptor (Lepr)-expressing perivascular stromal cells. Most HSCs were lost when Scf was deleted from both endothelial and Lepr-expressing perivascular cells. HSCs reside in a perivascular niche in which multiple cell types express factors that promote HSC maintenance.

                Author and article information

                Front Cell Dev Biol
                Front Cell Dev Biol
                Front. Cell Dev. Biol.
                Frontiers in Cell and Developmental Biology
                Frontiers Media S.A.
                13 June 2017
                : 5
                Department of Stem Cell Biology, Research Institute, National Center for Global Health and Medicine Tokyo, Japan
                Author notes

                Edited by: Marietta Herrmann, AO Foundation, Switzerland

                Reviewed by: César Nombela Arrieta, University of Zurich, Switzerland; Julien Y. Bertrand, Université de Genève, Switzerland; Eirini Trompouki, Max Planck Institute of Immunobiology and Epigenetics, Germany

                *Correspondence: Keiyo Takubo keiyot@

                This article was submitted to Stem Cell Research, a section of the journal Frontiers in Cell and Developmental Biology

                Copyright © 2017 Morikawa and Takubo.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Figures: 1, Tables: 3, Equations: 0, References: 78, Pages: 10, Words: 7826
                Cell and Developmental Biology


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