title: VMAT2 identified as a regulator of late-stage β-cell differentiation.
abstract: Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic β cells from pluripotent stem cells. Development of this technique has been hampered by a lack of knowledge of the molecular mechanisms underlying β-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 β-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 β cells that exhibited glucose-stimulated insulin secretion. When ES cell-derived β cells were transplanted into AKITA diabetic mice, the cells reversed hyperglycemia. Our protocol provides a basis for the understanding of β-cell differentiation and its application to a cost-effective production of functional β cells for cell therapy.
authors: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Daisuke
authors: D
authors: Sakano
authors: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Nobuaki
authors: N
authors: Shiraki
authors: 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.
authors: Kazuhide
authors: K
authors: Kikawa
authors: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Taiji
authors: T
authors: Yamazoe
authors: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Masateru
authors: M
authors: Kataoka
authors: Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan.
authors: Kahoko
authors: K
authors: Umeda
authors: Laboratory of Developmental Genetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto, Japan.
authors: Kimi
authors: K
authors: Araki
authors: Institute for Chemical Research and Institute for Integrated Cell-Material Sciences, (WPI-iCeMS), Kyoto University, Kyoto, Japan.
authors: Di
authors: D
authors: Mao
authors: Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Shirou
authors: S
authors: Matsumoto
authors: Division of Reproductive Engineering, Center for Animal Resources and Development, Kumamoto University, Kumamoto, Japan.
authors: Naomi
authors: N
authors: Nakagata
authors: 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.
authors: Olov
authors: O
authors: Andersson
authors: 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.
authors: Didier
authors: D
authors: Stainier
authors: Department of Pediatrics, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan.
authors: Fumio
authors: F
authors: Endo
authors: 1] Department of Stem Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan. [2].
authors: Kazuhiko
authors: K
authors: Kume
authors: Institute for Chemical Research and Institute for Integrated Cell-Material Sciences, (WPI-iCeMS), Kyoto University, Kyoto, Japan.
authors: Motonari
authors: M
authors: Uesugi
authors: 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.
authors: Shoen
authors: S
authors: Kume
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002454:Cell Differentiation; D003921:Diabetes Mellitus, Experimental; D053595:Embryonic Stem Cells / Q000187:drug effects; D006801:Humans; D006943:Hyperglycemia / Q000628:therapy; D050417:Insulin-Secreting Cells / Q000166:cytology* / Q000378:metabolism*; D051379:Mice; D015394:Molecular Structure; D012110:Reserpine / Q000737:chemistry / Q000494:pharmacology; D013747:Tetrabenazine / Q000737:chemistry / Q000494:pharmacology; D050493:Vesicular Monoamine Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018759:Adrenergic Uptake Inhibitors; D050493:Vesicular Monoamine Transport Proteins; D012110:Reserpine; D013747:Tetrabenazine