Amelioration of Congenital Tufting Enteropathy in EpCAM (TROP1)-Deficient Mice via Heterotopic Expression of TROP2 in Intestinal Epithelial Cells
Amelioration of Congenital Tufting Enteropathy in EpCAM (TROP1)-Deficient Mice via Heterotopic Expression of TROP2 in Intestinal Epithelial Cells
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DOI：
10.3390/cells9081847
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发表时间：
2020-08-01
期刊：
影响因子：
6
通讯作者：
Udey, Mark C.
中科院分区：
文献类型：
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作者：
Nakato, Gaku;Morimura, Sohshi;Udey, Mark C.
TROP1(EpCAM)和TROP2是同源的细胞表面蛋白，在发育中的和成体的上皮中广泛表达，而且经常是共表达的。EPCAM和TROP2具有多种功能，但相关机制尚不完全清楚，功能等价性尚未得到检验。成人肠上皮细胞(IEC)高表达EpCAM，而TROP2不表达。EpCAM缺乏会导致人类先天性簇状肠病(CTE)和相应的小鼠致死性疾病。我们利用绒毛蛋白启动子在EpCAM缺陷小鼠的IEC中表达了TROP2和EpCAM，以评估EpCAM和TROP2的功能。EpCAM基因敲除小鼠IEC中EpCAM或TROP2的表达可预防CTE。TROP2救援(T2R)小鼠比对照组小，而EPR(EPR)小鼠则不小。T2R小肠直径和组织学异常，Paneth和干细胞标记物减少。T2R小鼠还表现出肠系膜淋巴结增大，对4 kDa FITC-葡聚糖的通透性增加，对洗涤剂诱导的结肠炎的敏感性增加，这与屏障功能受损一致。对IEC类器官和类球体的研究表明，T2R小鼠的干细胞功能也受到了影响。我们得出结论：EpCAM和TROP2存在功能冗余，但它们并不等价。
TROP1 (EpCAM) and TROP2 are homologous cell surface proteins that are widely expressed, and often co-expressed, in developing and adult epithelia. Various functions have been ascribed to EpCAM and TROP2, but responsible mechanisms are incompletely characterized and functional equivalence has not been examined. Adult intestinal epithelial cells (IEC) express high levels of EpCAM, while TROP2 is not expressed. EpCAM deficiency causes congenital tufting enteropathy (CTE) in humans and a corresponding lethal condition in mice. We expressed TROP2 and EpCAM in the IEC of EpCAM-deficient mice utilizing a villin promoter to assess EpCAM and TROP2 function. Expression of EpCAM or TROP2 in the IEC of EpCAM knockout mice prevented CTE. TROP2 rescue (T2R) mice were smaller than controls, while EpCAM rescue (EpR) mice were not. Abnormalities were observed in the diameters and histology of T2R small intestine, and Paneth and stem cell markers were decreased. T2R mice also exhibited enlarged mesenteric lymph nodes, enhanced permeability to 4 kDa FITC-dextran and increased sensitivity to detergent-induced colitis, consistent with compromised barrier function. Studies of IEC organoids and spheroids revealed that stem cell function was also compromised in T2R mice. We conclude that EpCAM and TROP2 exhibit functional redundancy, but they are not equivalent.