Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn's disease recurrence.
Mitochondrial impairment drives intestinal stem cell transition into dysfunctional Paneth cells predicting Crohn's disease recurrence.
复制标题
DOI：
10.1136/gutjnl-2019-319514
复制
发表时间：
2020-11
期刊：
影响因子：
24.5
通讯作者：
Haller D
中科院分区：
文献类型：
--
作者：
Khaloian S;Rath E;Hammoudi N;Gleisinger E;Blutke A;Giesbertz P;Berger E;Metwaly A;Waldschmitt N;Allez M;Haller D
炎症性肠病中可观察到潘氏细胞(PC)数量减少，PC功能受损与克罗恩病(CD)的回肠发病有关。PC位于Lgr5+肠道干细胞(ISC)附近，线粒体对ISC的更新和分化至关重要。在这里，我们描述了炎症条件下ISC和PC的表现，并描述了线粒体功能在ISC生态位维持中的作用。来自CD患者的回肠组织样本、小鼠线粒体功能障碍模型(HSP60TFISC)和类CD回肠炎(Δ/ΔΔARE)，以及肠道器官类被用来表征PC和ISCs与线粒体功能的关系。在CD和肿瘤坏死因子Δ患者中，炎症与PC中溶菌酶阳性颗粒数量减少和隐窝区域LGR5表达减少有关。疾病相关的PC和ISC的改变在CD患者的非炎症组织区域持续存在，并预测了手术切除后疾病复发的风险。ISC特异性的Hsp60缺失和线粒体呼吸抑制将线粒体功能与PC表型异常联系在一起。与体内干细胞减少一致，发炎的肿瘤坏死因子Δ的隐窝是小鼠在体外无法生长成有机类化合物。二氯乙酸酯介导的抑制糖酵解，迫使细胞转移到线粒体呼吸，改善iSC巢功能和挽救肿瘤坏死因子Δ的能力，是小鼠来源的隐窝，形成有机类化合物。我们提供的证据表明，与炎症相关的肠上皮线粒体功能障碍会触发代谢失衡，导致干性减少和获得功能障碍的PC表型。阻断糖酵解可能是在CD发病机制中对抗PC功能障碍的一个新的药物靶点。
Reduced Paneth cell (PC) numbers are observed in inflammatory bowel diseases and impaired PC function contributes to the ileal pathogenesis of Crohn’s disease (CD). PCs reside in proximity to Lgr5+ intestinal stem cells (ISC) and mitochondria are critical for ISC-renewal and differentiation. Here, we characterise ISC and PC appearance under inflammatory conditions and describe the role of mitochondrial function for ISC niche-maintenance. Ileal tissue samples from patients with CD, mouse models for mitochondrial dysfunction (Hsp60Δ/ΔISC) and CD-like ileitis (TNFΔARE), and intestinal organoids were used to characterise PCs and ISCs in relation to mitochondrial function. In patients with CD and TNFΔARE mice, inflammation correlated with reduced numbers of Lysozyme-positive granules in PCs and decreased Lgr5 expression in crypt regions. Disease-associated changes in PC and ISC appearance persisted in non-inflamed tissue regions of patients with CD and predicted the risk of disease recurrence after surgical resection. ISC-specific deletion of Hsp60 and inhibition of mitochondrial respiration linked mitochondrial function to the aberrant PC phenotype. Consistent with reduced stemness in vivo, crypts from inflamed TNFΔARE mice fail to grow into organoids ex vivo. Dichloroacetate-mediated inhibition of glycolysis, forcing cells to shift to mitochondrial respiration, improved ISC niche function and rescued the ability of TNFΔARE mice-derived crypts to form organoids. We provide evidence that inflammation-associated mitochondrial dysfunction in the intestinal epithelium triggers a metabolic imbalance, causing reduced stemness and acquisition of a dysfunctional PC phenotype. Blocking glycolysis might be a novel drug target to antagonise PC dysfunction in the pathogenesis of CD.
登录
查看更多内容
DSRNA激活的蛋白激酶的诱导将线粒体展开的蛋白质反应与肠炎的发病机理联系起来。
影响因子：
24.5
作者：
Rath E;Berger E;Messlik A;Nunes T;Liu B;Kim SC;Hoogenraad N;Sans M;Sartor RB;Haller D
通讯作者：
Haller D
影响因子：
29
作者：
Donohoe DR;Garge N;Zhang X;Sun W;O'Connell TM;Bunger MK;Bultman SJ
通讯作者：
Bultman SJ
DOI：
10.1038/nrgastro.2010.39
发表时间：
2010-05
期刊：
Nature reviews. Gastroenterology & hepatology
影响因子：
--
作者：
通讯作者：
--
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
24.5
作者：
Fritz T;Niederreiter L;Adolph T;Blumberg RS;Kaser A
通讯作者：
Kaser A