Elucidation of changes in intracellular energy metabolism during pancreatic beta-cell differentiation and maturation

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K20902
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Multi-year Fund
• Review Section: 0902:General internal medicine and related fields
• Research Institution: Osaka University
• Principal Investigator: Sasaki Shugo 大阪大学, 大学院医学系研究科, 特任助教(常勤) (60908185)
• Project Period (FY): 2021-08-30 – 2023-03-31
• Keywords: 膵β細胞 / iPS細胞 / 脂肪酸代謝 / 糖尿病

Outline of Final Research Achievements

Regenerative medicine for diabetes has been attracting attention. In this study, we aimed to elucidate intracellular metabolic changes during differentiation and maturation of pancreatic β cells with a focus on lipid metabolism, and to improve the efficiency of human iPS cell-derived β-cell differentiation through modification of lipid metabolism. scRNA-seq analysis of late embryonic mouse β cells revealed that the expression pattern of glycolytic enzyme genes did not change significantly in the early stage of β cell differentiation, while the expression levels of de novo lipogenesis (DNL) -related enzyme genes were increased. Similarly, in human iPS cell-derived β-like cells, increased the expression levels of DNL-related genes and cellular lipid droplets were increased during differentiation. Furthermore, inhibition of PPARα action increased the expressions of the insulin gene and DNL-related genes, suggesting promoted induction of β-cell differentiation.

Free Research Field

糖尿病再生医療

Academic Significance and Societal Importance of the Research Achievements

糖尿病の根治を目指した代替β細胞による細胞治療のためには、ES細胞やiPS細胞といった多能性幹細胞からβ細胞や膵島を効率よく分化誘導させる必要がある。現状、最新の方法を用いても約半数の細胞しかβ細胞に分化せず、インスリン分泌能も本来のβ細胞と比べ未熟である。この解決にはβ細胞発生・分化の詳細な解析が必要である。本研究では、β細胞分化・成熟における脂質代謝・合成の重要性を高解像度のシングルセル解析およびヒトiPS細胞モデルを用いて調べうる限り初めて明らかにした。さらにPPARαを介した脂質代謝経路の修飾によりiPS細胞由来β細胞分化誘導効率の改善が示唆され、今後の臨床応用が期待される。