Investigation of regeneration of intestinal epithelium during graft-versus-host disease
Project/Area Number |
21K20885
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Research Category |
Grant-in-Aid for Research Activity Start-up
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Allocation Type | Multi-year Fund |
Review Section |
0902:General internal medicine and related fields
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Research Institution | National Hospital Organization, Kyushu Medical Center (Clinical Institute) |
Principal Investigator |
Shuichiro Takashima 独立行政法人国立病院機構九州医療センター(臨床研究センター), その他部局等, 血液内科医師 (70622116)
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Project Period (FY) |
2021-08-30 – 2023-03-31
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Project Status |
Completed (Fiscal Year 2022)
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Budget Amount *help |
¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
Fiscal Year 2022: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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Keywords | GVHD / 同種造血幹細胞移植 / 腸管オルガノイド / IFN-gamma / MYC / インターフェロンガンマ / 腸幹細胞 / 上皮再生 / 炎症性サイトカイン |
Outline of Research at the Start |
移植片対宿主病(GVHD)は同種造血幹細胞移植の重大な合併症であり、その克服は移植成績の向上に必須である。新規治療の開発にはその病態解明が必要であり、我々は主要標的臓器である腸管に注目した。腸管GVHDの病理組織像は同時進行する上皮細胞の傷害と再生で特徴づけられる。しかし炎症性サイトカインの上皮再生への関与は明らかになっていない。この研究課題では炎症性サイトカインがGVHDにおける上皮細胞の再生に直接かかわっている可能性についてヒト検体とマウスモデルを用いて検証する。
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Outline of Final Research Achievements |
In this project, based on the results of preliminary single cell RNA sequencing of mouse crypt epithelial cells from bone marrow transplantation (BMT) recipients, we hypothesized that interferon-gamma (IFNg) drives proliferation of intestinal epithelium through Myc expression in intestinal stem cells (ISCs) during graft-versus-host disease (GVHD). We found that IFNg stimulates proliferation of intestinal epithelium also in human in association with MYC upregulation using an intestinal organoid system. We next performed immunofluorescent staining of Myc protein after BMT. Ileal crypts from recipients of allogeneic BMT demonstrated greater Myc expression than crypts from non-GVHD syngeneic BMT recipients. Finally, treatment with the Myc inhibitor reduced both GVHD pathology scores and crypt loss, which is a marker of the ISC compartment injury, in allogeneic BMT recipients. These findings suggested Myc upregulation in the intestinal crypts may contributes to reduction of gut GVHD.
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Academic Significance and Societal Importance of the Research Achievements |
本研究課題では腸管上皮細胞のシングルセルRNAシークエンス解析の結果に基づいて腸管上皮細胞の免疫学的な再生メカニズムを明らかにした。腸管GVHDのように免疫学的な機序で障害がおこる病態で炎症サイトカインがどのように腸管上皮の再生にかかわっているかは解明されておらず、本研究の成果は複雑なGVHD病態への理解を深めるものである。さらに近年、GVHD治療に炎症性サイトカインのシグナルを遮断する薬剤が登場しつつある状況を考えると本研究成果は将来的なGVHD治療開発につながると考えられる。
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Report
(3 results)
Research Products
(6 results)
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[Presentation] T細胞はインターフェロンガンマと腸幹細胞のSTAT1を 介して上皮再生を促進する2022
Author(s)
Shuichiro Takashima, Roshan Sharma, Suze A. Jansen, Takahiro Ito, Winston Chang, Anastasiya Egorova, Jason Kuttiyara, Ya-Yuan Fu, Hiromi Iwasaki, Chen Liu, Nicolas Robine, Linas Mazutis, Caroline A. Lindemans, and Alan M. Hanash
Organizer
第84回日本血液学会学術集会
Related Report
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[Presentation] Donor-Derived Amphiregulin Drives CD4+ T Cell Expansion and Promotes Tissue Pathology after Experimental Allogeneic BMT2022
Author(s)
Takahiro Ito, Shuichiro Takashima, Marco Calafiore, Ya-Yuan Fu, Anastasiya Egorova, Jason Kuttiyara, Winston Chang, Paola Vinci, Viktor Arnhold, Dietmar Zaiss, Alan M. Hanash
Organizer
64th ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Immune-Mediated Reprogramming of Intestinal Stem Cells Drives STAT1-Dependent Myc Expression and Epithelial Regeneration in GI-Gvhd2021
Author(s)
Shuichiro Takashima, Roshan Sharma, Anastasiya Egorova, Jason Kuttiyara, Takahiro Ito, Winston Chang, Suze A Jansen, Chen Liu, Caroline Lindemans, Linas Mazutis, Nicolas Robine and Alan M Hanash
Organizer
63rd ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research
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[Presentation] Corticosteroid Treatment Impairs Epithelial Regeneration, Limiting Intestinal Recovery in Experimental Graft Vs Host Disease2021
Author(s)
Viktor Arnhold, Suze A Jansen, Winston Chang, Govindarajan Thangavelu, Paola Vinci, Shuichiro Takashima, Anastasiya Egorova, Jason Kuttiyara, Marliek van Hoesel, Chen Liu, Marco Calafiore, Bruce R. Blazar, Caroline Lindemans and Alan M Hanash
Organizer
63rd ASH Annual Meeting and Exposition
Related Report
Int'l Joint Research