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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711868.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
VMAT2 identified as a regulator of late-stage beta-cell differentiation
Authors:Sakano, D.; Shiraki, N.; Kikawa, K.; Yamazoe, T.; Kataoka, M.; Umeda, K.; Araki, K.; Mao, D.; Matsumoto, S.; Nakagata, N.; Andersson, O.; Stainier, D.; Endo, F.; Kume, K.; Uesugi, M.; Kume, S.
Date of Publication (YYYY-MM-DD):2014-02
Title of Journal:Nat Chem Biol
Volume:10
Issue / Number:2
Start Page:141
End Page:148
Audience:Not Specified
Abstract / Description:Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic beta cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying beta-cell differentiation. The present study identified reserpine and tetrabenazine (TBZ), both vesicular monoamine transporter 2 (VMAT2) inhibitors, as promoters of late-stage differentiation of Pdx1-positive pancreatic progenitor cells into Neurog3 (referred to henceforth as Ngn3)-positive endocrine precursors. VMAT2-controlled monoamines, such as dopamine, histamine and serotonin, negatively regulated beta-cell differentiation. Reserpine or TBZ acted additively with dibutyryl adenosine 3',5'-cyclic AMP, a cell-permeable cAMP analog, to potentiate differentiation of embryonic stem (ES) cells into beta cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived beta cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of beta-cell differentiation and its application to a cost-effective production of functional beta cells for cell therapy.
Free Keywords:Adrenergic Uptake Inhibitors/pharmacology; Animals; *Cell Differentiation; Diabetes Mellitus, Experimental; Embryonic Stem Cells/drug effects; Humans; Hyperglycemia/therapy; Insulin-Secreting Cells/*cytology/*metabolism; Mice; Molecular Structure; Reserpine/chemistry/pharmacology; Tetrabenazine/chemistry/pharmacology; Vesicular Monoamine Transport Proteins/antagonists &; inhibitors/genetics/*metabolism
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:1] Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan. [2] Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Laboratory of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan. Institute for Chemical Research and Institute for Integrated Cell-Material Sciences, (WPI-iCeMS), Kyoto University, Kyoto, Japan. Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan. Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan. 1] Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden. [2] Department of Biochemistry and Biophysics, University of California-San Francisco, San Francisco, California, USA. 1] Department of Cell and Molecular Biology, Karolinska Institute, Stockholm, Sweden. [2] Department of Developmental Genetics, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany. 1] Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan. [2]. 1] Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan. [2] Program for Leading Graduate Schools, Health Life Science Interdisciplinary and Global Oriented (HIGO) Program, Kumamoto University, Kumamoto, Japan. %^ 1435821975
Identifiers:ISSN:1552-4469 (Electronic) 1552-4450 (Linking) %R 10.1038/nchembio.1410
URL:http://www.ncbi.nlm.nih.gov/pubmed/24316738
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