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P024 Development of a treatment for short bowel syndrome using small intestinal organoids

Sugimoto, S.(1);Kobayashi, E.(2);Fujii, M.(3);Ohta, Y.(3);Ishikawa, K.(1);Nanki, K.(1);Hakamata, Y.(4);Kanai, T.(5);Sato, T.(1);

(1)Keio University School of Medicine, Department of Organoid Medicine- Department of Gastroenterology, Tokyo, Japan;(2)Keio University School of Medicine, Department of Organ Fabrication, Tokyo, Japan;(3)Keio University School of Medicine, Department of Organoid Medicine, Tokyo, Japan;(4)Nippon Veterinary and Life Science University, School of Veterinary Nursing and Technology, Tokyo, Japan;(5)Keio University School of Medicine, Department of Gastroenterology, Tokyo, Japan

Background

Massive small intestinal resection leads to short bowel syndrome (SBS), which is a severe malabsorption disorder. Crohn's disease is one of the most frequent cause of surgical removal of the small intestine in adults. Severe SBS patients need to receive permanent parenteral nutrition, which can cause serious complications. Intestinal transplantation currently remains the only curative option for such patients but has not widespread due to its high mortality/rejection rates. Here, we propose a concept to generate a rejection-free small intestinalized colon (SIC) by replacing the native colonic epithelium with small intestinal organoids. 

Methods

Human normal intestinal organoids and rat intestinal organoids derived from luciferase-expressing LEW transgenic rats were established and cultured as previously described (Fujii et al. Cell Stem Cell 2018). Human colon or ileum organoids were xenotransplanted onto the EDTA-injured colon of immunodeficient mice via transanal infusion as previously described (Sugimoto et al. Cell Stem Cell 2018). In LEW rats, a 4-cm segment of the ascending and proximal transverse colon was dissected with the preservation of the vasculature. After EDTA-based removal of the colon epithelium, rat colon or ileum organoids were transplanted in a blinded manner. Following organoid transplantation, the colon segment was fixed to the abdominal walls as stoma outlets for a week. Afterwards, organoid-transplanted colon segment was trimmed and interposed between the jejunum beginning and the ileocolic valve following total jejunoileum resection. Overall survival and detailed histological analyses were performed.

Results

Xenotransplanted human ileum organoids reconstituted nascent villus structures reminiscent of the ileum epithelium in mouse colon. Furthermore, ileum xenografts exhibited a formation of Lyve-1+ lacteal-like structure equipped with the absorption-related machinery, but not colon xenografts. In rats, engrafted ileum organoids initially formed crypt-like structures in the colostomy and, after interposition, they developed mature villus structures. The villus formation was small intestine-specific and flow-dependent. The SIC gained small intestinal function along with the remodelling of the underlying lymphovascular networks. Ileum organoid-transplanted rats exhibited milder body weight loss and significantly higher survival rate compared to colon organoid-transplanted rats.

Conclusion

The SIC with villus structure, intact vasculature and innervation, and the lacteal, had absorptive and peristalsis functions. Small intestinal organoid transplantation as cell source of the SIC ameliorated intestinal failure in a rat SBS model.

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