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      Zebrafish In-Vivo Screening for Compounds Amplifying Hematopoietic Stem and Progenitor Cells: - Preclinical Validation in Human CD34+ Stem and Progenitor Cells

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          Abstract

          The identification of small molecules that either increase the number and/or enhance the activity of human hematopoietic stem and progenitor cells (hHSPCs) during ex vivo expansion remains challenging. We used an unbiased in vivo chemical screen in a transgenic ( c-myb:EGFP) zebrafish embryo model and identified histone deacetylase inhibitors (HDACIs), particularly valproic acid (VPA), as significant enhancers of the number of phenotypic HSPCs, both in vivo and during ex vivo expansion. The long-term functionality of these expanded hHSPCs was verified in a xenotransplantation model with NSG mice. Interestingly, VPA increased CD34 + cell adhesion to primary mesenchymal stromal cells and reduced their in vitro chemokine-mediated migration capacity. In line with this, VPA-treated human CD34 + cells showed reduced homing and early engraftment in a xenograft transplant model, but retained their long-term engraftment potential in vivo, and maintained their differentiation ability both in vitro and in vivo. In summary, our data demonstrate that certain HDACIs lead to a net expansion of hHSPCs with retained long-term engraftment potential and could be further explored as candidate compounds to amplify ex-vivo engineered peripheral blood stem cells.

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          Most cited references 60

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          Wnt/beta-catenin signaling in development and disease.

           Hans Clevers (2006)
          A remarkable interdisciplinary effort has unraveled the WNT (Wingless and INT-1) signal transduction cascade over the last two decades. Wnt genes encode small secreted proteins that are found in all animal genomes. Wnt signaling is involved in virtually every aspect of embryonic development and also controls homeostatic self-renewal in a number of adult tissues. Germline mutations in the Wnt pathway cause several hereditary diseases, and somatic mutations are associated with cancer of the intestine and a variety of other tissues.
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            The epigenomics of cancer.

            Aberrant gene function and altered patterns of gene expression are key features of cancer. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause this dysregulation. Here, we review recent advances in understanding how epigenetic alterations participate in the earliest stages of neoplasia, including stem/precursor cell contributions, and discuss the growing implications of these advances for strategies to control cancer.
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              The bone marrow niche for haematopoietic stem cells.

              Niches are local tissue microenvironments that maintain and regulate stem cells. Haematopoiesis provides a model for understanding mammalian stem cells and their niches, but the haematopoietic stem cell (HSC) niche remains incompletely defined and beset by competing models. Recent progress has been made in elucidating the location and cellular components of the HSC niche in the bone marrow. The niche is perivascular, created partly by mesenchymal stromal cells and endothelial cells and often, but not always, located near trabecular bone. Outstanding questions concern the cellular complexity of the niche, the role of the endosteum and functional heterogeneity among perivascular microenvironments.
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                Author and article information

                Contributors
                michael.brand@biotec.tu-dresden.de
                martin.bornhaeuser@uniklinikum-dresden.de
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                21 September 2017
                21 September 2017
                2017
                : 7
                Affiliations
                [1 ]ISNI 0000 0001 1091 2917, GRID grid.412282.f, Department of Hematology/Oncology, Medical Clinic and Policlinic I, University Hospital, ; Dresden, Germany
                [2 ]ISNI 0000 0000 8583 7301, GRID grid.419239.4, Institute of Biofunctional Polymer Materials, Leibniz Institute for Polymer Research, Max Bergmann Center of Biomaterials, ; Dresden, Germany
                [3 ]ISNI 0000 0004 0492 0584, GRID grid.7497.d, German Cancer Research Center (DKFZ), ; Heidelberg, Germany
                [4 ]German Consortium for Translational Cancer Research (DKTK), partner site, Dresden, Germany
                [5 ]ISNI 0000 0001 2111 7257, GRID grid.4488.0, Deep Sequencing Group SFB655, Biotechnology Center, , Technical University of Dresden, ; Dresden, Germany
                [6 ]ISNI 0000 0001 2113 4567, GRID grid.419537.d, Max-Planck Institute of Molecular Cell Biology and Genetics, ; Dresden, Germany
                [7 ]ISNI 0000 0001 0262 7331, GRID grid.410718.b, Department of Hematology, University Hospital Essen, University of Duisburg, ; Essen, Germany
                [8 ]ISNI 0000 0001 2111 7257, GRID grid.4488.0, DFG-Center for Regenerative Therapies Dresden (CRTD) – Cluster of Excellence, Technical University of Dresden, ; Dresden, Germany
                Article
                12360
                10.1038/s41598-017-12360-0
                5608703
                28935977
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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