Massimino Luca, Parigi Tommaso Lorenzo, Riva Matteo, Nicolò Sabrina, Errico Carmela, Spanò Salvatore, Mino Sara, Bugatti Mattia, Frontali Alice, Scarfò Federico, Vignali Andrea, Municchi Andrea, Villanacci Vincenzo, Albarello Luca, Ponzoni Maurilio, Solitano Virginia, Malesci Alberto, Jairath Vipul, Peyrin-Biroulet Laurent, Sileri Pierpaolo, Danese Silvio, Ungaro Federica
IRCCS Ospedale San Raffaele, Gastroenterology and Digestive Endoscopy Department, Milan, Italy.
Università Vita-Salute San Raffaele, Faculty of Medicine, Milan, Italy.
J Crohns Colitis. 2025 Jul 18. doi: 10.1093/ecco-jcc/jjaf130.
Crohn's disease is a chronic inflammatory disease of the bowel, often complicated by fibrotic strictures, for which medical treatment is lacking, and surgery is commonly required. The mechanisms underlying the progression from chronic inflammation to fibrosis are not yet defined. We aim to unravel Crohn's disease pathogenesis using a cutting-edge computational pipeline combining several available tools.
Spatial transcriptomics was performed on 13 surgical specimens, including inflamed and fibrotic Crohn's disease tissues and healthy controls. The resulting spatial data were integrated with single-cell RNA sequencing to trace the cellular and molecular transitions from healthy intestine to fibrotic tissue. Ligand-receptor interaction and pseudotime analyses were employed to infer dynamic cell-cell communication networks and lineage trajectories. Key computational findings were validated through immunostaining in an independent cohort of Crohn's disease patients. Finally, the therapeutic relevance of the identified target was evaluated in a TNBS-induced chronic colitis mouse model upon CD38 inhibitor administration.
We demonstrated that intestinal cytoarchitecture was rearranged while chronic inflammation progressed. Crohn's disease-associated fibrosis evolved within the mesenchymal compartment, driven by PECAM2 signaling through PECAM1-CD38 interaction. In parallel, ApoA signaling, particularly APOA1-ABCA interaction, emerged as relevant for maintaining epithelial and stromal homeostasis, while its downregulation was associated with fibrosis development. Moreover, CD38 signaling inhibition effectively reduced colitis symptoms and colon thickening in the experimental TNBS-induced model of chronic inflammation.
Our results provide insights into CD38-driven fibrosis and indicate that PECAM2 signaling blockade could reduce the development of strictures in patients with Crohn's disease, potentially offering a new treatment target.
克罗恩病是一种肠道慢性炎症性疾病，常并发纤维化狭窄，目前缺乏有效的药物治疗，通常需要手术治疗。从慢性炎症发展到纤维化的潜在机制尚未明确。我们旨在通过结合多种现有工具的前沿计算流程来阐明克罗恩病的发病机制。
对13个手术标本进行空间转录组学分析，包括发炎和纤维化的克罗恩病组织以及健康对照。将所得的空间数据与单细胞RNA测序相结合，以追踪从健康肠道到纤维化组织的细胞和分子转变。采用配体 - 受体相互作用和伪时间分析来推断动态细胞间通信网络和谱系轨迹。通过在独立的克罗恩病患者队列中进行免疫染色来验证关键的计算结果。最后，在给予CD38抑制剂的TNBS诱导的慢性结肠炎小鼠模型中评估所确定靶点的治疗相关性。
我们证明，在慢性炎症进展过程中，肠道细胞结构发生了重排。克罗恩病相关纤维化在间充质区室内演变，由PECAM2通过PECAM1 - CD38相互作用发出的信号驱动。同时，载脂蛋白A信号，特别是APOA1 - ABCA相互作用，在维持上皮和基质稳态方面发挥作用，而其下调与纤维化发展相关。此外，在实验性TNBS诱导的慢性炎症模型中，抑制CD38信号可有效减轻结肠炎症状和结肠增厚。
我们的结果为CD38驱动的纤维化提供了见解，并表明阻断PECAM2信号可减少克罗恩病患者狭窄的发展，可能提供一个新的治疗靶点。
