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MCL1 Is Required for Maintenance of Intestinal Homeostasis and Prevention of Carcinogenesis in Mice.
Gastroenterology ( IF 29.4 ) Pub Date : 2020-03-14 , DOI: 10.1053/j.gastro.2020.03.017
Marc E Healy 1 , Yannick Boege 2 , Michael C Hodder 3 , Friederike Böhm 2 , Mohsen Malehmir 2 , Anna-Lena Scherr 4 , Jasna Jetzer 2 , Lap Kwan Chan 2 , Rossella Parrotta 2 , Kurt Jacobs 5 , Laure-Alix Clerbaux 1 , Susanne Kreutzer 2 , Andrew Campbell 6 , Ella Gilchrist 6 , Kathryn Gilroy 6 , Ann-Katrin Rodewald 2 , Hanna Honcharova-Biletska 2 , Roman Schimmer 2 , Karelia Vélez 5 , Simone Büeler 2 , Patrizia Cammareri 6 , Gabriela Kalna 6 , Anna S Wenning 7 , Kathy D McCoy 8 , Mercedes Gomez de Agüero 7 , Henning Schulze-Bergkamen 4 , Christoph S N Klose 9 , Kristian Unger 10 , Andrew J Macpherson 7 , Andreas E Moor 5 , Bruno Köhler 4 , Owen J Sansom 3 , Mathias Heikenwälder 11 , Achim Weber 1
Affiliation  

Background & Aims

Intestinal epithelial homeostasis depends on a tightly regulated balance between intestinal epithelial cell (IEC) death and proliferation. While the disruption of several IEC death regulating factors result in intestinal inflammation, the loss of the anti-apoptotic BCL2 family members BCL2 and BCL2L1 has no effect on intestinal homeostasis in mice. We investigated the functions of the antiapoptotic protein MCL1, another member of the BCL2 family, in intestinal homeostasis in mice.

Methods

We generated mice with IEC-specific disruption of Mcl1 (Mcl1ΔIEC mice) or tamoxifen-inducible IEC-specific disruption of Mcl1 (i-Mcl1ΔIEC mice); these mice and mice with full-length Mcl1 (controls) were raised under normal or germ-free conditions. Mice were analyzed by endoscopy and for intestinal epithelial barrier permeability. Intestinal tissues were analyzed by histology, in situ hybridization, proliferation assays, and immunoblots. Levels of calprotectin, a marker of intestinal inflammation, were measured in intestinal tissues and feces.

Results

Mcl1ΔIEC mice spontaneously developed apoptotic enterocolopathy, characterized by increased IEC apoptosis, hyperproliferative crypts, epithelial barrier dysfunction, and chronic inflammation. Loss of MCL1 retained intestinal crypts in a hyperproliferated state and prevented the differentiation of intestinal stem cells. Proliferation of intestinal stem cells in MCL1-deficient mice required WNT signaling and was associated with DNA damage accumulation. By 1 year of age, Mcl1ΔIEC mice developed intestinal tumors with morphologic and genetic features of human adenomas and carcinomas. Germ-free housing of Mcl1ΔIEC mice reduced markers of microbiota-induced intestinal inflammation but not tumor development.

Conclusion

The antiapoptotic protein MCL1, a member of the BCL2 family, is required for maintenance of intestinal homeostasis and prevention of carcinogenesis in mice. Loss of MCL1 results in development of intestinal carcinomas, even under germ-free conditions, and therefore does not involve microbe-induced chronic inflammation. Mcl1ΔIEC mice might be used to study apoptotic enterocolopathy and inflammatory bowel diseases.



中文翻译:

MCL1是维持肠道稳态和预防小鼠癌变所必需的。

背景与目标

肠上皮稳态取决于肠上皮细胞(IEC)死亡与增殖之间的紧密调节平衡。虽然破坏几个IEC死亡调节因子会导致肠道炎症,但抗凋亡BCL2家族成员BCL2和BCL2L1的丢失对小鼠肠道稳态没有影响。我们调查了小鼠肠内稳态中抗凋亡蛋白MCL1(BCL2家族的另一个成员)的功能。

方法

我们产生小鼠的特定IEC-中断MCL1MCL1 ΔIEC只小鼠)或他莫昔芬的可诱导的特定IEC-中断MCL1(I- MCL1 ΔIEC只小鼠); 这些小鼠和全长Mcl1的小鼠(对照)在正常或无菌条件下饲养。通过内窥镜检查和肠上皮屏障通透性分析小鼠。通过组织学,原位杂交,增殖测定和免疫印迹分析肠组织。在肠组织和粪便中测量钙卫蛋白(一种肠道炎症的标志物)的水平。

结果

MCL1 ΔIEC小鼠自发开发凋亡enterocolopathy,其特征在于增加的IEC凋亡,过度增殖性隐窝上皮屏障功能障碍,和慢性炎症。MCL1的丢失使肠道隐窝保持在过度增殖状态,并阻止了肠道干细胞的分化。MCL1缺陷小鼠中肠道干细胞的增殖需要WNT信号,并与DNA损伤积累有关。到1岁,MCL1 ΔIEC小鼠发展肠道肿瘤与人类的腺瘤和癌的形态学和遗传学特征。的无菌住房MCL1 ΔIEC减少小鼠菌群诱发的肠炎,但不是肿瘤发展的标志物。

结论

抗凋亡蛋白MCL1是BCL2家族的成员,是维持肠道稳态和预防小鼠癌变所必需的。MCL1的丢失甚至在无菌条件下也会导致肠癌的发生,因此不涉及微生物引起的慢性炎症。MCL1 ΔIEC老鼠可能被用来研究细胞凋亡enterocolopathy和炎性肠病。

更新日期:2020-03-14
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