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

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K09455
• 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): 2017-04-01 – 2020-03-31
• Keywords: 膵臓 / インスリン / ドーパミン / GPCR / iPS細胞

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.

Free Research Field

細胞生物学

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。