Schlafen 11 Is a Novel Target for Mucosal Regeneration in Ulcerative Colitis
Schlafen 11 Is a Novel Target for Mucosal Regeneration in Ulcerative Colitis
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DOI：
10.1093/ecco-jcc/jjab032
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发表时间：
2021-02-17
影响因子：
8
通讯作者：
Tsuchiya, Kiichiro
中科院分区：
文献类型：
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作者：
Watanabe, Sho;Nishimura, Ryu;Tsuchiya, Kiichiro
背景与目的：溃疡性结肠炎(UC)是一种慢性炎症性结肠疾病，病程难治。虽然UC治疗的目的是实现粘膜愈合，但慢性炎症引起的粘膜损伤的发病机制尚不清楚。因此，我们旨在通过建立体外和体内模拟UC的人源化模型来阐明粘膜损伤的分子机制。方法：通过60周的炎症刺激，建立人结肠有机化合物的体外模型。通过基因芯片分析，确定了长期炎症引起的粘膜损伤的关键基因。采用小鼠结肠粘膜异种移植的方法建立体内模型。结果：体外模型显示，长期炎症可导致机体发生不可逆转的变化：炎症反应、细胞凋亡和氧化应激，抑制细胞活力。该模型还在基因表达和表型水平上模拟了UC患者的器官。基因芯片分析显示，Schlafen11[SLFN11]是由长期炎症不可逆转地诱导的。SLFN11在UC粘膜中高表达，而在正常黏膜中不表达。SLFN11[SLFN11-KD]基因敲除可抑制炎症诱导的肠上皮细胞[IECS]凋亡。此外，SLFN11-KD提高了异种移植的成活率，并诱导了缓解期UC患者隐窝的再生改变。结论：利用人结肠器官建立了独特的体外和体内模拟UC模型。他们发现SLFN11在UC的粘膜损伤中具有重要意义，并显示了其作为粘膜再生的新靶点的潜力。
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.