Elucidation of pancreatic beta cell differentiation and maturation mechanism by monoamines

• Project/Area Number: 26461036
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Tokyo Institute of Technology
• Principal Investigator: Sakano Daisuke 東京工業大学, 生命理工学院, 助教 (40571039)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: インスリン / β細胞 / 分化 / 脱分化 / モノアミン / ドーパミン / 膵臓 / 膵β細胞 / 自己複製 / 分泌 / 低分子化合物 / 複製 / ＫＯマウス / ＶＭＡＴ２

Outline of Final Research Achievements

We screened compounds that promote cell proliferation of mouse pancreatic β cells using 3,000 low molecular weight compounds. As a result, Domperidon (DPD) which is an antagonist of dopamine D2 receptor (Drd2) was identified. And it was also revealed that DPD has a strong dedifferentiation suppressing effect and cell death suppressing effect in addition to an increase of self-replicating ability of β cell.
Furthermore, the formation of a heterodimer between Drd 2 and the adenosine A 2a receptoris important to control cell differentiation, dedifferentiation, cell division and cell death (Sakano et al., Stem Cell R eports, 2015).

Research Products

• [Journal Article] Dopamine D2 receptor-mediated regulation of pancreatic b cell mass. (2016)
  • Author(s): １.Sakano D, Choi S, Kataoka M, Shiraki N, Uesugi M, Kume K, Kume S
  • Journal Title: Stem Cell Reports Volume: ７ Issue: 1 Pages: 95-109
  • DOI: 10.1016/j.stemcr.2016.05.015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Pancreatic differentiation from murine embryonic stem cells. Methods Mol Biol. (2016)
  • Author(s): Sakano D, Shiraki N, Kuem S
  • Journal Title: Methods Mol Biol. Volume: 1341 Pages: 417-423
  • DOI: 10.1007/7651_2015_217
  • ISBN: 9781493929535, 9781493929542
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Beneficial effect of insulin treatment on islet transplantation outcomes in akita mice. (2014)
  • Author(s): Kikawa K, Sakano D, Shiraki N, Tsuyama T, Kume K, Endo F, Kume S.
  • Journal Title: Plos one Volume: 9(4) Issue: 4 Pages: e95451-e95451
  • DOI: 10.1371/journal.pone.0095451
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Generation of insulin-producing beta-like cells from human iPS cells in a defined and completely Xeno-free culture system. (2014)
  • Author(s): Shahjalal HM, Shiraki N, Sakano D, Kikawa H, Ogaki S, Baba H, Kume K., Kume S.
  • Journal Title: Journal of Molecular Cell Biology Volume: 6 Issue: 5 Pages: 394-408
  • DOI: 10.1093/jmcb/mju029
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] VMAT2 identified as a regulator of late-stage beta cell differentiation. (2013)
  • Author(s): Sakano, D., Shiraki, N., Kikawa, K., Yamazoe, T., Kataoka, M., Umeda, K., Araki, K., Mao, D., Matsumoto, S., Nakagata, N., Andersson, O., Stainier, D., Endo, F., Kume, K., Uesugi, M. and Kume, S.
  • Journal Title: Nat. Chem. Biol. Volume: 10 Issue: 2 Pages: 141-148
  • DOI: 10.1038/nchembio.1410
  • Peer Reviewed
• [Presentation] Monoamine signals that control differentiation and proliferation of pancreatic beta cells (2016)
  • Author(s): 粂 昭苑
  • Organizer: CDBシンポジウム２０１６
  • Place of Presentation: 理化学研究所 多細胞システム形成研究センター（CDB）
  • Year and Date: 2016-03-26
• [Presentation] モノアミンシグナルによる膵β細胞の増殖・分化の制御 (2016)
  • Author(s): 坂野大介、崔 成翼、片岡正光、白木伸明、粂昭苑
  • Organizer: 日本生化学会
  • Place of Presentation: 宮城県
• [Presentation] モノアミンシグナルによる膵β細胞の分化・増殖制御、 (2016)
  • Author(s): 坂野大介、崔 成翼、片岡正光、白木伸明、粂昭苑
  • Organizer: 厚生労働省「ヒト幹細胞情報化推進事業」SKIP Seminar
  • Place of Presentation: 東京都
  • Invited
• [Presentation] モノアミンを介したシグナル伝達による膵島の構造・機能の制御 (2015)
  • Author(s): 坂野大介
  • Organizer: 第3回細胞凝集研究会
  • Place of Presentation: 鹿児島
  • Year and Date: 2015-11-20
• [Presentation] Monoamine signals that control differentiation and proliferation of pancreatic beta cells. (2015)
  • Author(s): 粂 昭苑
  • Organizer: 2016 Keystone Symposia Conference T2: Diabetes: New Insights into Molecular Mechanisms and Therapeutic Strategies
  • Place of Presentation: 京都
  • Year and Date: 2015-10-27
  • Int'l Joint Research
• [Presentation] 膵β細胞の複製を促進する低分子化合物の探索 (2014)
  • Author(s): 坂野 大介、崔 成翼、片岡 正光、粂 昭苑
  • Organizer: 第37回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2014-11-25 – 2014-11-27
• [Book] 「膵β細胞研究の進化と展望」 『多能性幹細胞から膵β細胞への分化を制御するシグナル』Islet Equality (2014)
  • Author(s): 坂野大介、粂昭苑
  • Total Pages: 4
  • Publisher: メディカルレビュー社
• [Book] 「膵β細胞・膵島の再生研究」『特集 糖尿病-診断・治療update-』 (2014)
  • Author(s): 坂野大介、粂昭苑
  • Total Pages: 6
  • Publisher: 最新医学社
• [Book] 「糖尿病と代謝」『iPS細胞を用いた膵β細胞研究の最前線』、Diabetes Journal (2014)
  • Author(s): 坂野大介、粂昭苑
  • Total Pages: 6
  • Publisher: 協和企画
• [Book] 「膵島バイオロジーの新たな展開」『幹細胞を用いた膵β細胞誘導研究』、Diabetes Frontier (2014)
  • Author(s): 坂野大介、粂昭苑
  • Total Pages: 6
  • Publisher: 協和企画
• [Remarks] ドーパミンD2受容体を介して 膵臓のβ細胞量が調節される
  • URL: http://educ.titech.ac.jp/bio/news/2016_07/052422.html
• [Remarks] 多能性幹細胞分野 坂野大介助教、粂昭苑教授ら、マウスES細胞から膵臓細胞を作製することに成功しました
  • URL: http://kumanichi.com/news/local/main/20131216002.shtml
• [Remarks] 小胞型モノアミン輸送体VMAT2は膵臓β細胞の分化を制御する
  • URL: http://first.lifesciencedb.jp/archives/8151