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Organoids transplantation as a new modality to design epithelial signature to create a membrane-protective sulfomucin-enriched segment

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Abstract

Background

The organoids therapy for ulcerative colitis (UC) is under development. It is important to dissect how the engrafted epithelium can provide benefits for overcoming the vulnerability to inflammation. We mainly focused on the deliverability of sulfomucin, which is reported to play an important role in epithelial function.

Methods

We analyzed each segment of colon epithelium to determine differences in sulfomucin production in both mice and human. Subsequently, we transplanted organoids established from sulfomucin-enriched region into the injured recipient epithelium following dextran sulfate sodium-induced colitis and analyzed the engrafted epithelium in mouse model.

Results

In human normal colon, sulfomucin production was increased in proximal colon, whereas it was decreased in the inflammatory region of UC. In murine colon epithelium, increased sulfomucin production was found in cecum compared to distal small intestine and proximal colon. RNA sequencing analysis revealed that several key genes associated with sulfomucin production such as Papss2 and Slc26a1 were enriched in isolated murine cecum crypts. Then we established murine cecum organoids and transplanted them into the injured epithelium of distal colon. Although the expression of sulfomucin was temporally decreased in cecum organoids, its secretion was restored again in the engrafted patches after transplantation. Finally, we verified a part of mechanisms controlling sulfomucin production in human samples.

Conclusion

This study illustrated the deliverability of sulfomucin in the disease-relevant grafting model to design sulfomucin-producing epithelial units in severely injured distal colon. The current study is the basis for the better promotion of organoids transplantation therapy for refractory UC.

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Acknowledgements

We thank all members of the Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU) for their feedback on this study. We also thank Shintaro Akiyama, Department of Gastroenterology, Faculty of Medicine, University of Tsukuba for his commentary support on the manuscript. We also thank Ichiro Sekiya, Norio Shimizu, and all other members of Center for Stem cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU) for their feedback on this study.

Funding

This work was supported by MEXT/JSPS KAKENHI [18K15743 to SY; 20H03657 to SY; 19H01050 and 22H00472 to MW; 19H03634 to RO], Japan Agency for Medical Research and Development (AMED) [20bm0704029h0003 to SY; 20bm0304001h0008 and 20bk0104008h0003 to MW, 20bm0404055h0002 to RO], Japan Science and Technology Agency (JST) Forrest Program [JPMJFR2012 to SY], Young Innovative Medical Science Unit (TMDU) to SY, and Naoki Tsuchida Research Grant to SY.

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Author notes

  1. Satoshi Watanabe and Nobuhiko Ogasawara have contributed equally to this work.

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan

    Satoshi Watanabe, Nobuhiko Ogasawara, Sakurako Kobayashi, Sakura Kirino, Masami Inoue, Yui Hiraguri, Sayaka Nagata, Tomohiro Mizutani, Yasuhiro Nemoto & Ryuichi Okamoto

  2. Center for Stem Cell and Regenerative Medicine, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan

    Hiromichi Shimizu & Shiro Yui

  3. Advanced Research Institute, Tokyo Medical and Dental University (TMDU), Bunkyo-ku, Tokyo, 113-8510, Japan

    Go Ito & Mamoru Watanabe

  4. Department of Gastroenterology, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennoudai, TsukubaTsukuba, Ibaraki, 305-8575, Japan

    Kiichiro Tsuchiya

Authors
  1. Satoshi Watanabe
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  2. Nobuhiko Ogasawara
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  3. Sakurako Kobayashi
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  4. Sakura Kirino
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  14. Mamoru Watanabe
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Contributions

Conceptualization: SW, MW, SY. Methodology: SW, MW, SY. Investigation: SW, NO, SK, SK, MI, YH, SN, HS, GI, TM. Visualization: SW, NO, SY. Funding acquisition: MW, RO, SY. Sample offer: YN, KT, RO. Supervision: MW. Writing—original draft: SW, NO, SY.

Corresponding author

Correspondence to Shiro Yui.

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Conflict of interest

All authors declare no COI.

Data availability

RNA sequencing will be available from a corresponding author on reasonable request. Human organoids used in this study can be used only at TMDU according to the regulation of the study.

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Watanabe, S., Ogasawara, N., Kobayashi, S. et al. Organoids transplantation as a new modality to design epithelial signature to create a membrane-protective sulfomucin-enriched segment. J Gastroenterol 58, 379–393 (2023). https://doi.org/10.1007/s00535-023-01959-y

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  • DOI: https://doi.org/10.1007/s00535-023-01959-y

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