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Elucidation of monoamine-GPCR signal-regulated pancreatic beta cell differentiation and maturation mechanism

Research Project

Project/Area Number 17K09455
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionTokyo 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) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywords膵臓 / インスリン / ドーパミン / GPCR / iPS細胞 / 分化 / 膵β細胞 / iPS / 脱分化 / 糖尿病 / 再生医療
Outline of Final Research Achievements

Addition of a dopamine synthesis inhibitor or a monoamine transporter (VMAT2) inhibitor to the medium improves the differentiation efficiency and maturity of human iPS cell-derived β-like cells. The main cause of this was suppression of dedifferentiation.
Weak insulin secretion observed during the process of β-like cell differentiation and maturation suppressed an increase in the expression of genes that promote cell maturation. Furthermore, this insulin secretion promoted dedifferentiation. In addition, the proportion of cells having dopamine synthetic ability was different for each pancreatic islet. Dopamine, which is released extracellularly during insulin secretion, may be involved in heterogeneous maintenance of β-cell differentiation levels within the islets.

Academic Significance and Societal Importance of the Research Achievements

β細胞が主たる構成要素である膵島は内部のβ細胞が均一な分化・成熟化レベルではない。高い成熟度を維持し続けることは、β細胞の脱分化・細胞死につながることを本研究におけるマウス個体を用いた実験で実証した。今後、再生医療にヒトiPS細胞由来β様細胞を使用するうえで、より長期的かつ生体内に近い血糖値維持を達成するためには、生体内における膵島内の細胞間相互作用を理解、再現することが必要不可欠である。モノアミンを介した細胞間相互作用機構の一部を解明することができたことは、再生医療の実現化に貢献できたと考える。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (8 results)

All 2019 2017

All Presentation (8 results) (of which Int'l Joint Research: 1 results)

  • [Presentation] 膵β細胞の大量培養および成熟調節機構に関する研究2019

    • Author(s)
      小野 満里絵、坂野 大介、豊田 悠暉、荒木 菜、、粂 昭苑
    • Organizer
      日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Analysis of Vmat2 mediated regulation in insulin secretion2017

    • Author(s)
      Uefune F, Sonoda Y, Sakano D, Aonishi T, Kume S
    • Organizer
      International Diabetes Federation Congress 2017
    • Related Report
      2017 Research-status Report
    • Int'l Joint Research
  • [Presentation] モノアミンによるインスリン分泌制御機構の解明2017

    • Author(s)
      上船史弥、園田雄輝、坂野大介、青西亨、粂昭苑
    • Organizer
      50th Annual Meeting for the Japanese Society of Developmental Biologists
    • Related Report
      2017 Research-status Report
  • [Presentation] Establishment and analysis of hiPSC that visualize the INSULIN producing cells2017

    • Author(s)
      徳間 啓, Zixuan Erinn Sim, 上船 史弥, 坂野 大介, 白木 伸明, 粂 昭苑
    • Organizer
      第89回日本細胞生物学会大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Generation and Characterization of an INSULIN promoter driven mCherry Reporter Human iPS Cell Lines Using CRISPR/Cas9 system2017

    • Author(s)
      徳間 啓, Zixuan Erinn Sim, 上船 史弥, 坂野 大介, 白木 伸明, 粂 昭苑
    • Organizer
      日本発生生物学会第50回大会
    • Related Report
      2017 Research-status Report
  • [Presentation] Monoamine signaling controls cell differentiation and maturation of pancreatic beta cell2017

    • Author(s)
      Daisuke Sakano, Yuki Toyoda, Sai Araki, Nobuaki Shiraki, Shoen Kume
    • Organizer
      Conbio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] Signaling Pathway of Monoamine in Pancreatic β-cell Differentiation2017

    • Author(s)
      Sai Araki, Yuki Toyoda, Daisuke Sakano, Shoen Kume
    • Organizer
      Conbio2017
    • Related Report
      2017 Research-status Report
  • [Presentation] Monoamine controls differentiation and maturation state of pancreatic β-cells2017

    • Author(s)
      Yuki Toyoda, Sai Araki, Daisuke Sakano, Shoen Kume
    • Organizer
      Conbio2017
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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