Schlafen 11 Is a Novel Target for Mucosal Regeneration in Ulcerative Colitis

Autor:	Mariko Negi, Yuka Matsumoto, Ryuichi Okamoto, Ryu Nishimura, Nobuhiro Katsukura, Kiichiro Tsuchiya, Shuji Hibiya, Tetsuya Nakamura, Sho Watanabe, Susumu Kirimura, Tomoaki Shirasaki, Mamoru Watanabe
Rok vydání:	2021
Předmět:	Xenotransplantation medicine.medical_treatment Transplantation Heterologous Cell Culture Techniques Apoptosis Inflammation Inflammatory bowel disease Pathogenesis Mice In vivo Organoid medicine Animals Humans Regeneration Intestinal Mucosa business.industry Regeneration (biology) Gastroenterology Nuclear Proteins Epithelial Cells General Medicine medicine.disease Ulcerative colitis Organoids Disease Models Animal Cancer research Colitis Ulcerative medicine.symptom business
Zdroj:	Journal of Crohn's and Colitis. 15:1558-1572
ISSN:	1876-4479 1873-9946
DOI:	10.1093/ecco-jcc/jjab032
Popis:	Background and Aims Ulcerative colitis [UC] is a chronic inflammatory disease of the colon with an intractable course. Although the goal of UC therapy is to achieve mucosal healing, the pathogenesis of mucosal injury caused by chronic inflammation remains unknown. We therefore aim to elucidate molecular mechanisms of mucosal injury by establishing in vitro and in vivo humanised UC-mimicking models. Methods An in vitro model using human colon organoids was established by 60 weeks of inflammatory stimulation. The key gene for mucosal injury caused by long-term inflammation was identified by microarray analysis. An in vivo model was established by xenotransplantation of organoids into mouse colonic mucosa. Results An in vitro model demonstrated that long-term inflammation induced irrecoverable changes in organoids: inflammatory response and apoptosis with oxidative stress and suppression of cell viability. This model also mimicked organoids derived from patients with UC at the gene expression and phenotype levels. Microarray analysis revealed Schlafen11 [SLFN11] was irreversibly induced by long-term inflammation. Consistently, SLFN11 was highly expressed in UC mucosa but absent in normal mucosa. The knockdown of SLFN11 [SLFN11-KD] suppressed apoptosis of intestinal epithelial cells [IECs] induced by inflammation. Moreover, SLFN11-KD improved the take rates of xenotransplantation and induced the regenerative changes of crypts observed in patients with UC in remission. Conclusions In vitro and in vivo UC-mimicking models were uniquely established using human colonic organoids. They revealed that SLFN11 is significant for mucosal injury in UC, and demonstrated its potential as a novel target for mucosal regeneration.
Databáze:	OpenAIRE
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