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Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn’s disease strictures [Human scRNA-seq]

ABSTRACT: A significant complication of Crohn’s disease (CD) is intestinal fibrosis, which narrows the bowel lumen to cause a stricture. Creeping fat (CF) is the wrapping of mesenteric adipose tissue (MAT) around inflamed and fibrotic bowel, but its role in stricture progression in CD is unclear. In this study, we explore whether CF-derived fibroblasts, the cells primarily responsible for extracellular matrix (ECM) deposition, directly contribute to stricture progression. By performing scRNA-seq and Visium on pediatric CD strictures, we identified a CF-associated, mechanosensitive, CTHRC1+ fibroblast enriched for YAP/TAZ signaling that localized to the fibrotic CF-bowel wall interface within the stricture. We developed a novel mouse model of intestinal fibrosis that exhibited CF and used lineage tracing to show that Postn+ mouse fibroblasts, analogous to human CTHRC1+ fibroblasts, infiltrate fibrotic bowel and deposit ECM in a YAP/TAZ-dependent manner through scRNA-seq. Our findings identify mesenteric fat as a key source of pro-fibrotic fibroblasts that can be therapeutically targeted to limit intestinal fibrosis.

ORGANISM(S): Homo sapiens

PROVIDER: GSE275145 | GEO | 2025/08/23

REPOSITORIES: GEO

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Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn’s disease strictures [Visium]

Project description:A significant complication of Crohn’s disease (CD) is intestinal fibrosis, which narrows the bowel lumen to cause a stricture. Creeping fat (CF) is the wrapping of mesenteric adipose tissue (MAT) around inflamed and fibrotic bowel, but its role in stricture progression in CD is unclear. In this study, we explore whether CF-derived fibroblasts, the cells primarily responsible for extracellular matrix (ECM) deposition, directly contribute to stricture progression. By performing scRNA-seq and Visium on pediatric CD strictures, we identified a CF-associated, mechanosensitive, CTHRC1+ fibroblast enriched for YAP/TAZ signaling that localized to the fibrotic CF-bowel wall interface within the stricture. We developed a novel mouse model of intestinal fibrosis that exhibited CF and used lineage tracing to show that Postn+ mouse fibroblasts, analogous to human CTHRC1+ fibroblasts, infiltrate fibrotic bowel and deposit ECM in a YAP/TAZ-dependent manner through scRNA-seq. Our findings identify mesenteric fat as a key source of pro-fibrotic fibroblasts that can be therapeutically targeted to limit intestinal fibrosis.

2025-08-23 | GSE275144 | GEO

Creeping fat-derived mechanosensitive fibroblasts drive intestinal fibrosis in Crohn’s disease strictures [Mouse scRNA-seq]

2025-08-23 | GSE275148 | GEO

Single-cell RNAseq of mesenteric adipose tissue from Crohn's disease patients and healthy controls

Project description:As a hallmark of Crohn's disease (CD)，creeping fat (CF) is intimately related to intestinal fibrosis and postoperative recurrence. It is defined as expansion of mesenteric adipose tissue envelops the diseased intestinal segment. Compared with the healthy controls, CF has enriched functions related to adipogenesis and immune response.

2023-07-30 | GSE215001 | GEO

Integration of genome-wide DNA methylome and transcriptome of human intestinal fibroblasts reveals novel candidate gene signatures in Crohnâs disease-associated fibrosis

Project description:Tissue fibrosis is a serious complication of Crohnâs disease (CD) as well as of a variety of other complex, chronic pathologies. Understanding the underlying pathophysiology of tissue fibrosis is crucial for the development of tissue-specific prevention and interventional treatment strategies. To identify molecular states specific to fibrotic disease, we employed deep sequencing to define the genome-wide DNA methylome and the whole transcriptome of purified human intestinal fibrotic fibroblasts (HIFs) isolated from the colon of patients with fibrotic CD. Integration of this information, via computational tools, identified candidate molecular interactions that could lead to fibrosis pathology. Our definition of a genome-wide fibrosis-specific DNA methylome provides a new paradigm for understanding mechanisms of pathological gene expression that lead to intestinal fibrosis and may have relevance to fibrogenesis in other organs. Human intestinal fibroblasts (HIFs) were extracted and cultured from colon specimens of two groups: Crohnâs disease with associated fibrosis (n=3) and normal fibroblasts from patients with Diverticulitis (n=3). Both RNA-seq and MBD-isolated genome sequencing (MiGS) were performed on every sample.

2016-03-22 | E-GEOD-67250 | biostudies-arrayexpress

Prim-O-glucosylcimifugin Attenuates TGF-β-Induced Fibrosis via MAPK Pathway Inhibition and ECM Remodeling in Intestinal Fibroblasts

Project description:Background: Intestinal fibrosis is a major complication of inflammatory bowel disease (IBD), particularly Crohn’s disease, and often necessitates surgical intervention due to stricture formation. Despite progress in anti-inflammatory therapies, effective anti-fibrotic treatments remain lacking. Objective: This study evaluated the anti-fibrotic potential and underlying mechanisms of Prim-O-glucosylcimifugin (POG), a natural chromone derivative, in human intestinal fibroblasts. Methods: Fibrosis was induced in human intestinal fibroblast cell lines and primary fibroblasts by TGF-β1 (2 ng/mL). Cells were treated with POG, and fibrotic marker expression was assessed by immunofluorescence, qPCR, and Western blot. MMP1 activity and fibroblast migration were analyzed. Transcriptomic and integrative network analyses were performed to elucidate molecular mechanisms. Results: POG significantly suppressed TGF-β1-induced fibroblast activation, downregulating fibrotic markers (α-SMA, fibronectin, collagen I/III, N-cadherin) and inhibiting Smad and MAPK signaling. POG also promoted ECM degradation by upregulating MMP1 and suppressing TIMP1. Transcriptomic data confirmed regulation of pathways involved in ECM remodeling and MAPK signaling. POG displayed no cytotoxicity in intestinal epithelial cells. Conclusion: POG mitigates intestinal fibrosis by dual inhibition of TGF-β/Smad and MAPK pathways and by enhancing ECM degradation through selective modulation of the MMP1-TIMP1 axis. These findings support POG as a promising therapeutic candidate for intestinal fibrosis in IBD.

2025-05-18 | GSE297101 | GEO

Fibrosis associated changes detected in the proteome of surface epithelium overlying Crohn’s Disease Strictures

Project description:Background and aims: Intestinal fibrosis is a common complication of Crohn’s disease (CD). It is characterised by an excessive accumulation of fibroblasts differentiating into activated myofibroblasts secreting excessive extracellular matrix. The potential role of the intestinal epithelium in this fibrotic process remains poorly defined. Methods: A total of 113 CD and control subjects were studied. We performed a pilot proteomic study comparing the proteome of surface epithelium isolated by laser capture microdissection in normal and fibrotic zones of resected ileal CD strictures (n=5). Selected proteins were validated by immunohistochemistry (IHC) in colonic and ileal samples of stricturing CD patients (n=44), pure inflammatory CD (n=29) and control subjects (n=40). Functional assays with cell lines cultures and a fibroblast to myofibroblast differentiation model were used to assess the role of the highlighted epithelial proteins in CD fibrosis. Results: Proteomic study revealed an endoplasmic reticulum (ER) stress and unfolded protein response (UPR) markers increase in the epithelium overlying ileal fibrotic strictures, involving Anterior gradient protein 2 homolog (AGR2) and Binding immunoglobulin protein (BiP). This was confirmed by IHC. The ER stress induction in intestinal epithelial cells increased AGR2 as well as BiP expression and led to an extracellular secreted AGR2. A fibroblast to myofibroblast differentiation was obtained with the supernatant of intestinal epithelial cells pre-conditioned by ER stress and with recombinant AGR2. Conclusions: AGR2 and other ER stress markers are increased within the intestinal epithelium overlying fibrotic strictures and might contribute to profibrotic signals involved in CD fibrosis.

2022-04-04 | PXD022214 | Pride

Role of ZNF281 in intestinal fibroblast activation: new insights in IBD-related fibrosis

Project description:Serious complications of Crohn’s disease (CD), a form of Inflammatory Bowel Disease (IBD), involve the formation of intestinal fibrotic stenosis followed by obstruction. Chronic inflammatory state activates resident fibroblasts and myofibroblasts, that are the key effector cells in fibrosis, being responsible for the synthesis of ECM proteins. Exposure of human colon fibroblasts (CCD18-Co) to the pro-fibrotic cytokine TGF-β1 is sufficient to induce the expression of genes associated with myofibroblast features such as cell migration, ECM remodeling and contraction. Furthermore, during TGFβ1-mediated myofibroblast differentiation, the transcription factor ZNF281 is increased and is required to reshape the expression of genes encoding for myofibroblast markers, suggesting an active role for ZNF281 as a master regulator of intestinal myofibroblast functions.

2022-09-02 | GSE204868 | GEO

Single cell RNA-sequencing of cells isolated from full-thickness surgically resected tissue from stricturing and non-stricturing segments of the ileum of Crohn's disease patients

Project description:Intestinal fibrosis and stricture formation is an aggressive complication of Crohn’s disease (CD) and there is a clear unmet need for new therapies based on a better understanding of disease mechanisms. Knowledge of fibroblast heterogeneity is important as disease-state specific cell types represent important therapeutic targets. A lack of validated cell markers currently hampers progress.

2023-10-24 | E-MTAB-11792 | biostudies-arrayexpress

Integration of genome-wide DNA methylome and transcriptome of human intestinal fibroblasts reveals novel candidate gene signatures in Crohn’s disease-associated fibrosis

Project description:Tissue fibrosis is a serious complication of Crohn’s disease (CD) as well as of a variety of other complex, chronic pathologies. Understanding the underlying pathophysiology of tissue fibrosis is crucial for the development of tissue-specific prevention and interventional treatment strategies. To identify molecular states specific to fibrotic disease, we employed deep sequencing to define the genome-wide DNA methylome and the whole transcriptome of purified human intestinal fibrotic fibroblasts (HIFs) isolated from the colon of patients with fibrotic CD. Integration of this information, via computational tools, identified candidate molecular interactions that could lead to fibrosis pathology. Our definition of a genome-wide fibrosis-specific DNA methylome provides a new paradigm for understanding mechanisms of pathological gene expression that lead to intestinal fibrosis and may have relevance to fibrogenesis in other organs.

2016-03-22 | GSE67250 | GEO

Osteopontin Regulation of MerTK+ Macrophages Promotes Crohn’s Disease Intestinal Fibrosis

Project description:The pathogenesis of intestinal fibrosis in Crohn’s disease (CD) remains unclear. Mer receptor tyrosine kinase (MerTK) is an immunosuppressive protein specifically expressed in macrophages. Osteopontin (OPN), also known as secreted phosphoprotein 1, contributes to inflammation and wound repair. This study investigates the potential profibrotic pathway in MerTK+ macrophages in order to provide a possible therapeutic target for intestinal fibrosis. MerTK expression in the inflamed and stenotic bowels was evaluated. The MerTK/ERK/TGF-β1 pathway was overactivated in the fibrotic intestinal tissues of patients with CD. This pathway was induced by epithelial cell apoptosis, resulting in activated fibroblasts with increased TGF-β1 secretion. OPN upregulated TGF production by altering ERK1/2 phosphorylation, as evidenced by OPN or MerTK knockdown and OPN overexpression in vitro. MerTK inhibitor UNC2025 alleviated intestinal fibrosis in mouse colitis models, suggesting a potential therapeutic target for intestinal fibrosis in patients with CD.

2024-05-31 | PXD052743 |

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