The mechanism for the maintenance of pancreatic beta cells derived by in vitro differentiation of human pluripotent stem cells
| Project/Area Number |
18H02861
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Review Section |
Basic Section 54040:Metabolism and endocrinology-related
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| Research Institution | Tokyo Institute of Technology |
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Principal Investigator |
Kume Shoen 東京工業大学, 生命理工学院, 教授 (70347011)
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| Project Period (FY) |
2018-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000)
Fiscal Year 2020: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2019: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
Fiscal Year 2018: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000)
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| Keywords | 膵臓β細胞 / ドパミン / VMAT2 / インスリン分泌 / 膵臓 / 内分泌細胞 / 血糖維持 / 分化 / 多能性幹細胞 / インスリン / 糖代謝 / 増殖 / 膵臓分化 / 内胚葉 / 糖尿病 / 分化誘導 / 恒常性維持 / 分泌 |
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| Outline of Final Research Achievements |
VMAT2 plays a significant negative regulatory role in the transmission of dopamine. βVMAT2KO beta cells (or WT beta-cells treated with VMAT2 inhibitor TBZ) cannot uptake dopamine into vesicles; thus, dopamine is subjected to degradation by MAO, leading to a reduced dopamine content and an increased generation of ROS. The decreased dopamine content leads to a reduction in the dopamine negative feedback loop which, in turn, leads to elevated insulin secretion. Under HFD conditions, where excess nutrient stress exists, insulin secretion occurs frequently, increasing beta-cell exposure to ROS. Long-term exposure to ROS leads to increased vulnerability of βVMAT2KO beta-cells and accelerated beta-cell failure. βVMAT2KO beta-cells show an initial compensation via beta-cell growth and increased beta-cell mass followed by dedifferentiation and beta-cell death, which is a characteristic of the progression of beta-cell failure.
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| Academic Significance and Societal Importance of the Research Achievements |
VMAT2-ドパミンシグナルは膵臓β細胞の分化抑制シグナルとして働くのみならず、β細胞の量を制御するシグナルでもあり、糖応答性インスリン分泌を負に制御するシグナルである。一方、VMAT2-ドパミンシグナルを欠くと、糖応答性インスリン分泌が亢進した。高脂肪食給餌条件下では、β細胞特異的VMAT2遺伝子変異マウスは、対照の野生型よりも早く耐糖能の改悪を示し、β細胞の脱分化、脱落を引き起こした。これらの結果から、膵臓β細胞を正常に維持するためには、負に制御するシグナルが重要な役割を果たすことが示された。膵臓β細胞の恒常性維持のためには、その機能を適宜に制御することが重要であることが示された。
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Report
(4 results)
Research Products
(37 results)
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[Journal Article] Dietary sodium chloride attenuates increased β-cell mass to cause glucose intolerance in mice under a high-fat diet.2021
Author(s)
Taki K, Takagi H, Hirose T, Sun R., Yaginuma H, Mizoguchi A, Kobayashi T, Sugiyama M, Tsunekawa T, Onoue T, Hagiwara D, Ito Y, Iwama S, Suga H, Banno R, Sakano D, Kume S, Arima H,
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Journal Title
Plos One
Volume: 16
Issue: 3
Pages: e0248065-e0248065
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Generation of human induced pluripotent stem cell-derived functional enterocyte-like cells for pharmacokinetic studies2021
Author(s)
Yoshida S, Honjo T, Iino K, Ishibe R, Leo S, Shimada T, Watanabe T, Ishikawa M, Maeda K, Kusuhara H, Shiraki N, Kume S.
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Journal Title
Stem Cell Reports
Volume: 16
Issue: 2
Pages: 295-308
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Collagen vitrigel promotes hepatocytic differentiation of induced pluripotent stem cells into functional hepatocyte-like cells.2019
Author(s)
Nakai S, Shibata I, Shitamichi T, Yamaguchi H, Takagi N, Inoue T, Nakagawa T, Kiyokawa J, Wakabayashi S, Miyoshi T, Higashi E, Ishida S, Shiraki N, Kume S
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Journal Title
Biology Open
Volume: 8
Pages: 042192-042192
DOI
Related Report
Peer Reviewed / Open Access
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[Journal Article] Inhibition of Cdk5 Promotes β-cell differentiation from ductal progenitors2018
Author(s)
Liu KC, Leuckx G, Sakano D, Seymour PA, Mattssona CL, Rautioa L, Verdonck Yannick, Serup P, Kume S, Heimberg H, Andersson O
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Journal Title
Diabetes
Volume: 67
Issue: 1
Pages: 58-70
DOI
Related Report
Peer Reviewed / Int'l Joint Research
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