VMAT2 identified as a regulator of late-stage [beta]-cell differentiation

• Published in: Nature chemical biology Vol. 10; no. 2; p. 141
• Main Authors: Sakano, Daisuke, Shiraki, Nobuaki, Kikawa, Kazuhide, Yamazoe, Taiji, Kataoka, Masateru, Umeda, Kahoko, Araki, Kimi, Mao, Di, Matsumoto, Shirou, Nakagata, Naomi, Andersson, Olov, Stainier, Didier, Endo, Fumio, Kume, Kazuhiko, Uesugi, Motonari, Kume, Shoen
• Format: Journal Article
• Language: English
• Published: Cambridge Nature Publishing Group 01.02.2014
• Subjects: Cell differentiation; Cell growth; Cellular biology; Diabetes; Histamine; Inhibitors; Insulin; Pancreas; Stem cells
• ISSN: 1552-4450; 1552-4469
• DOI: 10.1038/nchembio.1410

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.