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01.01.2019 | Original Article—Alimentary Tract

Establishment of a system to evaluate the therapeutic effect and the dynamics of an investigational drug on ulcerative colitis using human colonic organoids

Zeitschrift:
Journal of Gastroenterology
Autoren:
Ryu Nishimura, Tomoaki Shirasaki, Kiichiro Tsuchiya, Yoshihide Miyake, Yusuke Watanabe, Shuji Hibiya, Sho Watanabe, Tetsuya Nakamura, Mamoru Watanabe
Wichtige Hinweise

Electronic supplementary material

The online version of this article (https://​doi.​org/​10.​1007/​s00535-018-01540-y) contains supplementary material, which is available to authorized users.
Ryu Nishimura, Tomoaki Shirasaki and Kiichiro Tsuchiya equally contributed to this article.

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Abstract

Background

Ulcerative colitis (UC) is a chronic inflammatory disease of the colon with an intractable, recurrent course. The goal of UC therapy is to target mucosal healing because immune-suppressive therapy for UC frequently results in relapse. However, few drugs directly target mucosal healing. We, therefore, aim to evaluate the therapeutic effect of an investigational drug on intestinal epithelial cells in an in vitro UC model using human colonic organoids.

Methods

Colonic organoids were isolated from human colon and cultured. A mixture of cytokines and bacterial components were used to mimic UC in humans. The effect of the investigational drug on colonic organoid was evaluated by microarray analysis and 3D immunofluorescence. The enrichment of stem cells was assessed with a colony formation assay.

Results

Inflammatory stimulation resulted in a significant induction of inflammatory-related genes in colonic organoids whereas cell differentiation was suppressed. Treatment with the investigational drug KAG-308 showed reciprocal dynamics of gene expression to inflammatory stimulation, which resulted in not only the suppression of immune response but also the promotion of cellular differentiation towards secretory lineages. Moreover, SPDEF and Reg4 were identified as novel targets for the enrichment of intestinal epithelial stem cells and mucosal healing.

Conclusions

The establishment of in vitro UC model using human colonic organoid could reveal the effects and targets of investigational drugs in intestinal epithelial cells under inflammation conditions. Further maturation of this system might be more efficient to predict the effect on UC, as compared with the use of animal model, for the development of new drugs.

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Zusatzmaterial
Supplementary material 1 (PDF 1502 kb)
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Supplementary material 2 (PDF 9352 kb)
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Supplementary material 3 (PDF 2932 kb)
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Supplementary material 4 (PDF 3541 kb)
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Supplementary material 5 (PDF 3529 kb)
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Supplementary material 6 (PDF 10088 kb)
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Supplementary material 7 (PDF 404 kb)
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Supplementary material 8 (PDF 417 kb)
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Supplementary material 9 (DOC 77 kb)
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Supplementary material 10 (DOCX 17 kb)
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Supplementary material 11 (DOCX 23 kb)
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Supplementary material 12 (DOCX 19 kb)
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Supplementary material 13 (DOCX 19 kb)
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Literatur
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