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 2

Meflin deficiency aggravates intestinal fibrosis in the DSS-induced colitis model.

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Meflin deficiency aggravates intestinal fibrosis in the DSS-induced coli...
(A) ISH for Meflin (Islr) in the mouse colon. Arrowheads denote Meflin+ cells. SM, submucosa; MP, musclularis propria. (B) Schematic diagram of DSS-induced chronic colitis and fibrosis model. (C and D) Colonic tissue sections from WT mice at different time points after DSS administration are examined by H&E staining, IHC for α-SMA, Sirius Red staining (C), and ISH for Meflin (D). Note that muscularis mucosa thickness is increased over time (arrowheads). Quantification (n = 3–5/group). Arrows denote Meflin+ cells. 1-way ANOVA. (E) Representative images of H&E-stained colon sections from WT and Meflin-KO mice after 9 weeks of DSS administration (n = 7 and 4 for WT and Meflin-KO mice, respectively), followed by the quantification of submucosa thickness. (F and G) Representative images of IHC for α-SMA (F) and Sirius Red staining (G) on colon sections from WT and Meflin-KO mice after DSS administration, followed by the quantifications of α-SMA–positive areas, collagen layer thickness, Sirius Red+ areas, and fibrosis score. (C–G) Five 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. 2-tailed Student’s t tests unless otherwise indicated. *P < 0.05; **P < 0.01; ****P < 0.0001.