Elucidation of PPY cell lineage for development of new beta cell origin

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K08984
• 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: Saitama Medical University
• Principal Investigator: Hara Akemi 埼玉医科大学, 医学部, 非常勤講師 (60570009)
• Co-Investigator(Kenkyū-buntansha): 藤谷 与士夫 群馬大学, 生体調節研究所, 教授 (30433783) ; 中尾 啓子 埼玉医科大学, 医学部, 講師 (70338185)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: β細胞 / Virgin β細胞 / PP細胞 / α細胞 / 分化転換 / 膵島 / 電気穿孔法

Outline of Final Research Achievements

To elucidate the gene functions that regulate the maintenance of differentiated traits in β-cells, it is necessary to analyze the function of each gene in individual cells under conditions unaffected by physiological changes. We transfected the rat insulinII promoter-Cre plasmid into the pancreas of Pdx1f/f or f/+ or +/+; Rosa26-eYFP mice by electroporation. Then, Virginβ (Vβ) cells in the peripheral region of pancreatic islets were selectively labeled and lineage traced. The analysis revealed that YFP-expressing Vβ cells in the gene-transfected islet peripheral region migrated to the core region of the islet. Furthermore, a decrease in Pdx1 gene concentration in undifferentiated β cells located in the islet peripheral region induced differentiation conversion from undifferentiated β cells to α cells or PP cells, indicating that there are regional differences in the rate of differentiation conversion in the pancreas.

Free Research Field

細胞生物学

Academic Significance and Societal Importance of the Research Achievements

我々の電気穿孔法は、①膵炎を惹起しないため炎症による影響を受けず、導入遺伝子は局所的に導入され②ホストとなるマウスの遺伝子型により、導入遺伝子の発現量を調節できる③遺伝子導入により組み換えが起きた遺伝子を長期的に発現させることが可能④膵島内で、目的遺伝子欠損細胞と非欠損細胞が存在することとなりモザイク解析が可能であり、このような膵島への遺伝子導入法は、世界でも未だ報告がない。我々の研究成果は、単一のβ細胞における遺伝子発現変化による分化転換制御機構を、個体の恒常性を保持した条件で解明した結果で、「真のβ細胞の性質」を解明する一歩となり、今後、新たな糖尿病治療法の開発への応用が期待できる。