Journal
NATURE CHEMICAL BIOLOGY
Volume 10, Issue 2, Pages 141-148Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nchembio.1410
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Funding
- Funding Program for Next Generation World-Leading Researchers [LS099]
- Japan Society for the Promotion of Science
- Realization of Regenerative Medicine
- Program for Leading Graduate Schools 'HIGO'
- Ministry of Education, Culture, Sports, Science and Technology (MEXT), Japan [21390280, 22790653]
- Collaborative Research Program of Institute for Chemical Research, Kyoto University [2010-44]
- World Premier International Research Center Initiative, MEXT, Japan
- Grants-in-Aid for Scientific Research [26253059, 22790653, 21390280, 23310135, 24115712] Funding Source: KAKEN
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Cell replacement therapy for diabetes mellitus requires cost-effective generation of high-quality, insulin-producing, pancreatic 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 p 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.
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