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Effects of TGF‐α gene knockout on epithelial cell kinetics and repair of methotrexate‐induced damage in mouse small intestine
Author(s) -
Xian Cory J.,
Cool Jo C.,
Howarth Gordon S.,
Read Leanna C.
Publication year - 2002
Publication title -
journal of cellular physiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.529
H-Index - 174
eISSN - 1097-4652
pISSN - 0021-9541
DOI - 10.1002/jcp.10079
Subject(s) - gene knockout , biology , knockout mouse , crypt , apoptosis , small intestine , transforming growth factor , microbiology and biotechnology , cancer research , immunology , endocrinology , receptor , gene , biochemistry
While previous studies have indicated that exogenous TGF‐α stimulates epithelial growth, maintenance, and repair of the gut, roles of endogenous TGF‐α are less well‐defined particularly in the small bowel. The current study examined effects of TGF‐α knockout on adult small intestinal epithelial cell proliferation, migration, apoptosis, and damage/repair response after methotrexate treatment. Compared to normal mice, TGF‐α gene knockout did not affect crypt cell production, mitosis position, migration, and apoptosis in non‐injured intestine. RT‐PCR gene expression analysis revealed presence of four out of six TGF‐α related EGF family ligands in the normal intestine, suggesting a possible functional redundancy of the EGF family in maintenance of the intestine. Although TGF‐α gene knockout did not significantly impair the overall mucosal repair in methotrexate‐induced acute damage in the small intestine, it resulted in a higher apoptotic response in the early hours following methotrexate challenge, and a delayed and reduced crypt cell proliferation during repair. Consistently, after methotrexate challenge, intestinal TGF‐α mRNA was found to be markedly upregulated in the early hours and during repair in the wild type, and there were similar profiles in the increased expression of all other ligands (except EGF) between the wild type and knockout intestines. Therefore, despite a possible functional redundancy among the EGF family ligands in the normal small intestine, TGF‐α may play a role in modulating the early apoptotic events and in enhancing the subsequent reparative proliferative response in the methotrexate‐damaged intestine. J. Cell. Physiol. 191: 105–115, 2002. © 2002 Wiley‐Liss, Inc.