DepartmentStem Cell Biology
Publication date25-Dec-2013

Daisuke Sakano, Nobuaki Shiraki, Kazuhide Kikawa, Taiji Yamazoe, Masateru Kataoka, Kahoko Umeda, Kimi Araki, Di Mao, Naomi Nakagata, Shirou Matsumoto, Olov Andersson, Didier Stainier, Fumio Endo, Kazuhiko Kume, Motonari Uesugi and Shoen Kume. (2013) VMAT2 identified as a regulator of late-stage β cell differentiation. Nature Chemical Biology. DOI: 10.1038/NCHEMBIO.1410

Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic b 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 (Figure) . 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 b cells for cell therapy.



ES cells differentiate through the mesendoderm, the definitive endoderm, pancreatic progenitor s and the endocrine progenitor stage, until mature β-cells. The cytosolic monoamine storage decreases when VMAT2 is inhibited. It leads to the increasing of the β-cell induction rate . This is through promoting differentiation of endocrine progenitors from pancreatic progenitors. Moreover, cell permeable cAMP renders the glucose-dependent insulin secreting abilities. It is possible to induce mature β -cell s by using VMAT2 inhibitor and cAMP.