Translational Research Center for Gastrointestinal Disorders (TARGID), Department of Chronic Diseases and Metabolism, KU Leuven, Leuven, Belgium.
Centre for Inflammation Research, University of Edinburgh, Edinburgh, United Kingdom.
J Clin Invest. 2024 Jul 23;134(16):e173835. doi: 10.1172/JCI173835.
Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.
克罗恩病（CD）的特征是反复发作的肠道炎症和组织损伤，常导致纤维性狭窄和肠梗阻，需要手术干预，但复发率高。为了阐明 CD 中纤维性狭窄的机制，我们分析了从 CD 患者的透壁回肠中分离出的细胞的转录组，包括每位患者的三联病变样本：未受影响、炎症和狭窄的回肠样本，并将其与没有 CD 的患者的样本进行比较。我们的计算分析表明，表达 CD150 的一组单核细胞衍生细胞的促纤维化信号诱导了一种疾病特异性成纤维细胞群体，导致慢性炎症和组织纤维化。转录因子 TWIST1 被确定为成纤维细胞激活和细胞外基质（ECM）沉积的关键调节剂。TWIST1 的遗传和药物抑制可防止成纤维细胞激活，减少 ECM 的产生和胶原沉积。我们的研究结果表明，髓基质轴可能是预防 CD 中纤维性狭窄的一个有前途的治疗靶点。
