Mechanisms of muscularis mucosa formation and collapse on gastric organoids derived from human-induced pluripotent stem cell

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17048
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Kobe University
• Principal Investigator: Uehara Keiichiro 神戸大学, 医学部附属病院, 助教 (70710557)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: iPS細胞 / 胃分化誘導 / 粘膜筋板

Outline of Final Research Achievements

Human gastric development has not been well studied. The generation of human pluripotent stem cell-derived gastric organoids (hGOs) comprising gastric marker-expressing epithelium without an apparent smooth muscle structure has been reported. We modified previously reported protocols to generate hGOs with muscularis mucosa (MM) from hiPSCs. Time-course analyses revealed that epithelium development occurred prior to MM formation. Sonic Hedgehog (SHH) and TGF-β1 were secreted by the epithelium. HH and TGF-β signal inhibition prevented MM formation. A mechanical property of the substrate promoted MM formation around hGOs. TGF-β signaling was shown to influence the HH signaling and mechanical properties. In addition, clinical specimen findings suggested the involvement of TGF-β signaling in MM regeneration. HH and TGF-β signaling from the epithelium to the stroma and the mechanical properties of the subepithelial environment may influence the emergence of MM in human stomach tissue.

Free Research Field

病理診断学

Academic Significance and Societal Importance of the Research Achievements

ヒトiPS細胞由来胃オルガノイドを用いて、粘膜筋板形成に胃上皮由来のヘッジホッグシグナル、TGF-βシグナル、基質の機械的環境が協同的に作用していることを初めて明らかにした。また、TGF-βシグナルは粘膜筋板再生の際にも作用している可能性が示唆された。今後、胃癌において粘膜筋板が再生することなく粘膜下層に浸潤するメカニズムを明らかできる可能性があり、新たな胃癌治療の標的を探索することができるものと考えられる。