Creation of pharmacokinetics and toxicity prediction model system using human iPS cell-derived small intestinal cells and tissues

2021 Fiscal Year Final Research Report

• Project/Area Number: 19H03391
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Nagoya City University
• Principal Investigator: Matsunaga Tamihide 名古屋市立大学, 医薬学総合研究院(薬学), 教授 (40209581)
• Co-Investigator(Kenkyū-buntansha): 岩尾 岳洋 名古屋市立大学, 医薬学総合研究院(薬学), 准教授 (50581740)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ヒトiPS細胞 / 小腸上皮細胞 / 小腸オルガノイド / 腸管デバイス / 小腸モデル

Outline of Final Research Achievements

We used gellan gum (GG), a soluble dietary fiber, to optimize human iPS cell-derived enterocytes (hiPSEs) differentiation. hiPSEs cocultured with GG had significantly higher expression of small intestine- and pharmacokinetics-related genes and proteins. GG could improve the differentiation efficiency of human iPS cells to enterocytes and increase intestinal maturation by extending the life span of hiPSEs. Human iPS cell-derived budding-like organoids showed a high expression of drug transporters and induced the expression of CYP3A4 and P-glycoprotein. Upon dissociation and seeding on cell culture inserts, the organoids retained intestinal characteristics, forming polarized intestinal folds with approximately 400 Ω×cm2 transepithelial electrical resistance. We generated small intestine-on-a-chip and construct with human iPS cell-derived 2D organoids. These novel methods have great potential for disease modeling and drug screening applications.

Free Research Field

幹細胞生物学

Academic Significance and Societal Importance of the Research Achievements

現在、消化管における薬物動態や毒性の評価にはヒト結腸ガン由来のCaco-2細胞などが用いられているがヒト正常小腸と機能が大きく異なる。また、消化管毒性の評価には、単一細胞系であるCaco-2細胞は適さない。本研究においてヒトiPS細胞から生体に匹敵する機能を有する小腸上皮細胞や小腸オルガノイドを作製する分化誘導法並びに培養法を開発した。また、小腸デバイスの開発を行い、試作品の作成並びに細胞培養の予備的試験を行った。これらの結果より、創薬研究等における薬物動態や毒性試験のより高精度な小腸モデル系の創製が可能となり、創薬研究支援材料として有用であることが示唆された。