Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine
Hepatocyte growth factor activator inhibitor-2 stabilizes Epcam and maintains epithelial organization in the mouse intestine
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DOI：
10.1038/s42003-018-0255-8
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发表时间：
2019-01-04
影响因子：
5.9
通讯作者：
Kataoka, Hiroaki
中科院分区：
文献类型：
--
作者：
Kawaguchi, Makiko;Yamamoto, Koji;Kataoka, Hiroaki
编码上皮丝氨酸蛋白酶抑制物肝细胞生长因子激活物抑制物-2(HAI-2)的SPINT2突变与先天性簇状肠病有关。然而，HAI-2在体内的功能还知之甚少。在这里，我们使用他莫昔芬诱导的Cre-loxP重组来去除Spint2。缺乏Spint2的小鼠在开始接受他莫昔芬治疗后的6天内死亡，整个肠道显示出严重的上皮损伤，肝外胆管也受到严重损害。肠上皮细胞剥脱加重，绒毛萎缩，肠上皮细胞丛生，隐窝延长。器官隐窝培养表明，Spint2消融导致Epcam裂解，Claudin-7水平降低，并导致器官破裂。这些器质性改变可以通过添加丝氨酸蛋白酶抑制剂抑肽酶、甲磺酸异氰酸酯和床垫选择性的α-酮苯并噻唑以及编码丝氨酸蛋白酶前列腺素的Prss 8的共同缺失来挽救。这些结果表明，HAI-2是维持肠上皮结构所必需的细胞抑制物。
Mutations in SPINT2 encoding the epithelial serine protease inhibitor hepatocyte growth factor activator inhibitor-2 (HAI-2) are associated with congenital tufting enteropathy. However, the functions of HAI-2 in vivo are poorly understood. Here we used tamoxifeninduced Cre-LoxP recombination in mice to ablate Spint2. Mice lacking Spint2 died within 6 days after initiating tamoxifen treatment and showed severe epithelial damage in the whole intestinal tracts, and, to a lesser extent, the extrahepatic bile duct. The intestinal epithelium showed enhanced exfoliation, villous atrophy, enterocyte tufts and elongated crypts. Organoid crypt culture indicated that Spint2 ablation induced Epcam cleavage with decreased claudin-7 levels and resulted in organoid rupture. These organoid changes could be rescued by addition of serine protease inhibitors aprotinin, camostat mesilate and matriptaseselective alpha-ketobenzothiazole as well as by co-deletion of Prss8, encoding the serine protease prostasin. These results indicate that HAI-2 is an essential cellular inhibitor for maintaining intestinal epithelium architecture.