Deciphering alpha-cell heterogeneity using a novel reporter mouse

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08895
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54040:Metabolism and endocrinology-related
• Research Institution: Juntendo University
• Principal Investigator: Ogihara Takeshi 順天堂大学, 医学部, 准教授 (60399772)
• Co-Investigator(Kenkyū-buntansha): 宮塚 健 順天堂大学, 大学院医学研究科, 客員教授 (60622363)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: α細胞 / 膵発生 / 内分泌細胞 / グルカゴン / 糖尿病再生医療

Outline of Final Research Achievements

Glucagon-expressing pancreatic alpha cells have been shown to play roles in glucose metabolism, although it remains unclear precisely when and where alpha cells emerge from and what regulates alpha-cell fate. We therefore explored the spatial and transcriptional heterogeneity of alpha-cell differentiation, using a novel time-resolved mouse model, ‘Gcg-Timer’, in which newly generated alpha cells can be distinguished from more differentiated cells by their fluorescence. Fluorescence imaging and flow cytometry with Gcg-Timer mice demonstrated that green-fluorescent cells were observed in Gcg-Timer mice at the embryonic and neonatal stages, but not after 1 week of age. Transcriptome analysis of Gcg-Timer embryos revealed that the mRNAs related to angiogenesis were enriched in newborn alpha cells. Histological analysis revealed that some newborn alpha cells arise close to the pancreatic ducts, whereas the others arise away from the ducts and adjacent to the blood vessels.

Free Research Field

β細胞再生医療

Academic Significance and Societal Importance of the Research Achievements

糖代謝・アミノ酸代謝においてグルカゴンが重要な役割を担っていることが解明されているが、グルカゴン分泌の制御機構やグルカゴン産生細胞であるα細胞の発生・分化機構の詳細は未解明である。本研究はα細胞の新生・分化過程を高時間分解能で解析する世界初の研究である。α細胞新生が胎生期に特化した現象であること、そして膵管または血管近傍においてのみ起こることは、β細胞新生過程とほぼ同様の知見であり、膵内分泌細胞に共通した特性である可能性がある。また本研究で開発した高時間分解能の時空間解析は他の細胞系譜にも応用可能であり、器官形成の統合的理解に役立つ。