IGF-I and procollagen α1(I) are coexpressed in a subset of mesenchymal cells in active Crohn's disease

Abstract

This study tested the hypothesis that insulin-like growth factor I (IGF-I) expression is increased at sites of fibrosis in diseased intestine of patients with Crohn's disease (CD). IGF-I mRNA was quantified by RNase protection assay in uninvolved and involved intestine of 13 CD patients (10 ileum, 3 colon) and 7 ulcerative colitis (UC) patients (colon). In situ hybridization histochemistry compared the localization of IGF-I and procollagen alpha1(I) mRNAs. Masson's trichrome staining and immunohistochemistry for IGF-I precursor, alpha-smooth muscle actin (A), vimentin (V), desmin (D), and c-kit were used to examine the mesenchymal cell subtypes that express IGF-I and collagen in uninvolved and involved ileum and colon of CD patients and "normal" ileum and colon from noninflammatory controls. IGF-I mRNA was elevated in involved ileum and colon of patients with CD but not in involved colon of patients with UC. IGF-I and procollagen alpha1(I) mRNA showed overlapping distribution within fibrotic submucosa and muscularis propria of involved CD ileum and colon. In involved CD intestine, increased IGF-I precursor expression localized to mesenchymal cells in regions of tissue disorganization and fibrosis in muscularis mucosa, submucosa, and muscularis propria. In these regions, there were increased numbers of V(+) cells relative to normal or uninvolved intestine. Increased IGF-I expression was localized to cells with a phenotype typical of fibroblasts (V(+)/A(-)/D(-)), myofibroblasts (V(+)/A(+)/D(+)), and, to a lesser extent, cells with normal enteric smooth muscle phenotype (V(-)/A(+)/D(+)). We conclude that increased IGF-I expression in multiple mesenchymal cell subtypes and increased numbers of cells with fibroblast/myofibroblast phenotype are involved in fibrosis associated with CD.

Endogenous IGF-I and αvβ3 integrin ligands regulate increased smooth muscle growth in TNBS-induced colitis

“…Upregulation of IGF-I expression is a common feature of chronically inflamed intestine whether in animal models of colitis or in Crohn's disease (16,24,37). Within the muscle layer, IGF-I plays an important role in the regulation of smooth muscle cell growth: it jointly stimulates growth and inhibits apoptosis (10,11).…”

Anti-melanin-concentrating hormone treatment attenuates chronic experimental colitis and fibrosis

“…TGF-␤ signaling results in phosphorylation of Smad2 and Smad3, which in turn form a complex with Smad4 and translocate to the nucleus, where they regulate transcription of several genes, including procollagen and fibronectin, extracellular matrix-degrading enzymes (MMPs), and their inhibitors (TIMP1, TIMP6), as well as regulators of mesenchymal cell proliferation and apoptosis (17). Beside TGF-␤, IGF-1 and TNF-␣ have also been shown to stimulate type I collagen synthesis, and their expression is increased in collagen deposition areas in the intestine of patients with CD (36,41).…”

“…Although transient appearance of myofibroblasts contributes to mucosal healing, their sustained proliferation and activation in response to chronic inflammation leads to intestinal fibrosis. Indeed, increased numbers of myofibroblasts were found in the affected mucosa of patients with CD and in mouse models of IBD (36).…”

Altered molecular pattern of mucosal healing in Crohn’s disease fibrotic stenosis

“…A final explanation could be an irreversible transformation of different type of cells into the fibrogenic phenotype, thus provoking the prevalence of fibrotic on inflammatory stenotic lesions [22] . During this process the exceeding of extracellular matrix cannot be inhibited by the regulatory mechanisms of the phenomenon according to what hypothesized by Pucilowska et al [23,24] . A speculative clinical consideration of our results may be the need of an accurate evaluation in the case of stenosis in the course of CD using all diagnostic available tools (histology, ultrasonography with Doppler evaluation of resistance index, biochemical indices of inflammation) in order to distinguish inflammatory from fibrotic stenosis.…”