Meflin confers antifibrotic properties to intestinal fibroblasts in inflammatory bowel disease
Jingxi Mu, Keiko Maeda, Tadashi Iida, Shinji Mii, Nobutoshi Esaki, Yukihiro Shiraki, Yasuyuki Mizutani, Masanao Nakamura, Takeshi Yamamura, Tsunaki Sawada, Eri Ishikawa, Kentaro Murate, Takashi Hirose, Kazuhiro Furukawa, Akina Oishi, Haruhiko Suzuki, Takayoshi Kishida, Goro Nakayama, Mitsuhiro Fujishiro, Hiroki Kawashima, Atsushi Enomoto
Jingxi Mu, Keiko Maeda, Tadashi Iida, Shinji Mii, Nobutoshi Esaki, Yukihiro Shiraki, Yasuyuki Mizutani, Masanao Nakamura, Takeshi Yamamura, Tsunaki Sawada, Eri Ishikawa, Kentaro Murate, Takashi Hirose, Kazuhiro Furukawa, Akina Oishi, Haruhiko Suzuki, Takayoshi Kishida, Goro Nakayama, Mitsuhiro Fujishiro, Hiroki Kawashima, Atsushi Enomoto
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Research Article Gastroenterology Inflammation

Meflin confers antifibrotic properties to intestinal fibroblasts in inflammatory bowel disease

Abstract

Dysfunctional intestinal fibrosis is an irreversible complication of Crohn’s disease (CD). The complex heterogeneity of intestinal mesenchymal cells makes it difficult to understand the pathogenesis of intestinal fibrosis. Previously, we identified Meflin as a marker of fibroblast subsets. This study aimed to explore the role of Meflin-positive fibroblasts in intestinal fibrogenesis and investigate the potential of pharmacological control of Meflin expression as a treatment for patients with CD. Our results indicated that Meflin expression was upregulated in fibroblasts at the early stage of fibrosis but was downregulated in established fibrosis in both patients with CD and 2 different mouse models, which are the chronic dextran sodium sulfate (DSS) model and an IL-10–deficient model that spontaneously develops intestinal inflammation. Meflin-deficient mice exacerbated intestinal fibrosis with dysregulated expression of noncanonical Wnt ligand WNT5A and its receptor ROR2. Pharmacologically induced Meflin expression through the administration of a synthetic retinoid reversed intestinal fibrosis in the DSS model and suppressed profibrotic protein secretion in fibroblasts isolated from patients with CD. Our findings indicate that Meflin-positive fibroblasts represent a functional subpopulation that suppresses intestinal fibrosis. Augmentation of Meflin expression shows antifibrotic effects and holds promise as a therapeutic approach for intestinal fibrosis in patients with CD.

Authors

Jingxi Mu, Keiko Maeda, Tadashi Iida, Shinji Mii, Nobutoshi Esaki, Yukihiro Shiraki, Yasuyuki Mizutani, Masanao Nakamura, Takeshi Yamamura, Tsunaki Sawada, Eri Ishikawa, Kentaro Murate, Takashi Hirose, Kazuhiro Furukawa, Akina Oishi, Haruhiko Suzuki, Takayoshi Kishida, Goro Nakayama, Mitsuhiro Fujishiro, Hiroki Kawashima, Atsushi Enomoto

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Figure 9

Dysregulated Wnt signaling in Meflin-deficient mice.

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Dysregulated Wnt signaling in Meflin-deficient mice. (A) Colon tissue se...
(A) Colon tissue sections prepared from intestines of WT mice treated with DSS are stained for Meflin (Islr, red) and Wnt5a (green) mRNA by FISH (left), followed by quantification of the positivity of Wnt5a in Meflin+ fibroblasts (arrows) (right). Boxed areas are magnified in insets (n = 3 per group). (B–F) Colon tissue sections prepared from the intestines of WT and Meflin-KO mice treated with DSS are stained for Wnt5a (B), Ror2 (C), Axin2 (D), Rspo3 (E), and Wls (F) using ISH or FISH (left panels), followed by quantification of the numbers of positive cells and percentage of those cells per all stromal cells with a fibroblast-like morphology (right panels). (n = 3–4 for each group). Arrows indicate the positive cells. (G) Schematic illustration showing the hypothesis proposed by the present study. (A–F) 5 HPFs per area were quantified for each mouse. Small gray dots indicate individual HPFs, and black triangles indicate mouse-level means used for statistical analysis. Scale bars: 40 μm. Statistical significance was determined using 2-tailed Student’s t tests. *P < 0.05; **P < 0.01; ***P < 0.001.