{
  "abstract": "Background Fibrostenosis is a common and disabling complication of Crohn’s disease (CD) with no reliable early biomarkers, limited treatment options and high postoperative recurrence.Objective To investigate the contribution of glioma-associated oncogene homolog 1 (GLI1+) mesenchymal cells to fibrostenotic progression and their potential as a therapeutic target.Design Fibrotic and non-fibrotic tissue samples were collected from patients with CD undergoing surgery for fibrostenotic obstruction. Chronic colitis was induced in mice using dextran sodium sulfate (DSS) or 2,4,6-trinitrobenzene sulfonic acid (TNBS). Single-cell RNA sequencing was performed on human and murine intestinal tissues. Gli1-CreERT2; R26-tdTomato and Gli1-CreERT2; R26-iDTR mice were used for lineage tracing and targeted cell ablation. GLI1+ mesenchymal cells were isolated to identify pathogenic determinants. A surgical CD fibrostenosis cohort was analysed.Results Single-cell transcriptomics and immunofluorescence revealed enrichment of GLI1+ mesenchymal cells at fibrotic sites. Lineage tracing showed that these cells expanded and adopted a myofibroblast phenotype in chronic colitis, whereas their ablation alleviated fibrosis. GLI1+ mesenchymal cells exhibited a distinct transcriptional expression profile with prominent expression of SPARC-related modular calcium-binding protein 2 (SMOC2). SMOC2 was upregulated in human and murine fibrosis, and its knockdown in vivo and in vitro attenuated fibrosis. Mechanistically, GLI1+ mesenchymal cells secreted SMOC2, promoting extracellular matrix deposition and fibroblast activation. In surgical CD cohorts, high SMOC2 expression in intestinal tissue correlated with postoperative recurrence, confirmed in the validation cohort.Conclusion GLI1+ mesenchymal cells drive intestinal fibrostenosis through SMOC2-mediated niche formation. SMOC2 may serve as a predictive biomarker for postoperative recurrence and a potential therapeutic target for CD.",
  "authors": [
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Danshu Wang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Xiangyu Zhao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Qidi Yang"
    },
    {
      "affiliations": [
        "Department of Critical Care Medicine, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Dehao Zhu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Yijing Liao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Yizhou Zhao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Sishen Sun"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Jiaxin Wang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Haiming Zhuang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Shuowen Zhang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Xinyu Wang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Tianyi Che"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Mingji Li"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Yubei Gu"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Jing Sun"
    },
    {
      "affiliations": [
        "State Key Laboratory of Chemo and Biosensing, Hunan Research Center of the Basic Discipline for Cell Signaling, College of Biology, Hunan University, Changsha, Hunan, China"
      ],
      "name": "Ningbo Wu"
    },
    {
      "affiliations": [
        "Shanghai Institute of Immunology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Jiao Tong University School of Medicine, Shanghai, China"
      ],
      "name": "Youqiong Ye"
    },
    {
      "affiliations": [
        "Sun Yat-sen University First Affiliated Hospital Department of Gastroenterology, Guangzhou, Guangdong, China"
      ],
      "name": "Ren Mao"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Yao Zhang"
    },
    {
      "affiliations": [
        "Department of Gastroenterology, Shanghai Jiao Tong University Medical School Affiliated Ruijin Hospital, Shanghai, China"
      ],
      "name": "Duowu Zou"
    }
  ],
  "title": "SMOC2 mediates GLI1+ mesenchymal cell-driven fibrostenosis and predicts postoperative recurrence in Crohn’s disease",
  "uid": "af2f23c5-34a2-51f9-b6e1-1ee0d6e97f49"
}