2022 Fiscal Year Final Research Report
Title of Research Project
| Project/Area Number |
20K21610
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 54:Internal medicine of the bio-information integration and related fields
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| Research Institution | Hokkaido University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
坂本 直哉 北海道大学, 医学研究院, 教授 (10334418)
冨塚 一磨 東京薬科大学, 生命科学部, 教授 (40444640)
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| Project Period (FY) |
2020-07-30 – 2023-03-31
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| Keywords | GVHD / TGF-beta / 肝幹細胞 / オーガノイド |
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| Outline of Final Research Achievements |
We investigated fate of liver stem cells in liver GVHD after allogeneic hematopoietic stem cell transplantation (allo-SCT). After allo-SCT, donor T cells and macrophages infiltrated in the portal area of the liver with apoptosis of the adjunct bile duct epithelial cells. Using Lgr5-eGFP-reporter mice, Lgr5+ cells isolated from the liver after allo-SCT were cultured to generate liver organoids. Number of the organoids was significantly decreased after allo-SCT. PCR analysis showed an upregulated expression of IFN-gamma, TGF, and TNF in the liver. Addition of TGF-beta suppressed the organoid formation in culture. Addition of TGF-beta inhibitor SB-431552 abrogated inhibitory effect of TGF-beta on the organoid formation. Administration of SB-431552 to mice after allo-SCT restored the organoid formation. These results indicated that macrophage-derived TGF-beta damage liver stem cells in GVHD.
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| Free Research Field |
血液内科学・造血細胞移植
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| Academic Significance and Societal Importance of the Research Achievements |
同種造血幹細胞移植の組織傷害はドナーT細胞が組織幹細胞を標的とすることによる組織恒常性、修復、細菌叢などの破綻によるものであることを我々は、腸、皮膚で明らかにしてきた。残るのは肝臓GVHDであったが、ここでも同様に胆管上皮幹細胞が標的となることを世界で最初に明らかにすることができた。さらにマクロファージ由来のTGF-betaがその原因であることを明らかにできたことで、将来的な新たな治療開発への展開が期待される。
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