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 1

Downregulation of Meflin expression in fibroblasts in the intestinal stricture regions.

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Downregulation of Meflin expression in fibroblasts in the intestinal str...
(A) Normalized Meflin (ISLR) mRNA expression in colon tissue biopsies obtained from non-IBD healthy individuals (n = 80) and patients with CD (n = 48). (B) UMAP feature plots show Meflin (ISLR) expression in stromal cell clusters but not in epithelial and immune cells. (C) UMAP feature plots showing normalized PDGFRA, PDPN, and ACTA2, and expressions in the stromal cell cluster. The arrows indicate cell clusters that coexpress Meflin, PDGFRA, and PDPN. The solid arrowhead indicates the cluster in the top right, which shows high ACTA2 expression but lacks Meflin expression. (D) FISH analysis for Meflin (red) and either PDGFRA (green, left panel) or ACTA2 (green, right panel) in the submucosal layer of the CD-affected intestine. Boxed areas are magnified in insets. Arrows denote double-positive cells. (E) Representative macroscopic image of the ileum surgically resected from a patient with CD. Stricture and nonstricture areas are indicated with arrowheads (left panel) and quantitative real-time polymerase chain reaction (qPCR) analysis for Meflin (right panel, n = 10 pairs). (F) Representative images of Meflin ISH in intestinal tissue sections from non-IBD and nonstricture and stricture areas of patients with CD (Case 1 and 2) and their quantification. Arrows denote Meflin+ cells. (G) Intestinal tissue sections of patients with CD were analyzed by IHC for α-SMA, followed by quantification of α-SMA-positive areas. (H) qPCR analysis of the intestines from patients with CD (n = 10 pairs). (F and G) 5 high-power fields (HPFs) per area were quantified for each patient. Small gray dots indicate individual HPFs, and black triangles indicate patient-level means used for statistical analysis. Paired samples from 10 patients were analyzed. Scale bars: 40 μm. 2-tailed t tests. *P < 0.05; **P < 0.01; ***P < 0.001.