牛奶脂肪球表皮生长因子 8（MFGE8）可预防肠道纤维化。
Milk fat globule-epidermal growth factor 8 (MFGE8) prevents intestinal fibrosis.
机构信息
Department of Gastroenterology and Hepatology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio, USA.
出版信息
Gut. 2024 Jun 6;73(7):1110-1123. doi: 10.1136/gutjnl-2022-328608.
OBJECTIVE
Intestinal fibrosis is considered an inevitable consequence of chronic IBD, leading to stricture formation and need for surgery. During the process of fibrogenesis, extracellular matrix (ECM) components critically regulate the function of mesenchymal cells. We characterised the composition and function of ECM in fibrostenosing Crohn's disease (CD) and control tissues.
DESIGN
Decellularised full-thickness intestinal tissue platforms were tested using three different protocols, and ECM composition in different tissue phenotypes was explored by proteomics and validated by quantitative PCR (qPCR) and immunohistochemistry. Primary human intestinal myofibroblasts (HIMFs) treated with milk fat globule-epidermal growth factor 8 (MFGE8) were evaluated regarding the mechanism of their antifibrotic response, and the action of MFGE8 was tested in two experimental intestinal fibrosis models.
RESULTS
We established and validated an optimal decellularisation protocol for intestinal IBD tissues. Matrisome analysis revealed elevated MFGE8 expression in CD strictured (CDs) tissue, which was confirmed at the mRNA and protein levels. Treatment with MFGE8 inhibited ECM production in normal control HIMF but not CDs HIMF. Next-generation sequencing uncovered functionally relevant integrin-mediated signalling pathways, and blockade of integrin αvβ5 and focal adhesion kinase rendered HIMF non-responsive to MFGE8. MFGE8 prevented and reversed experimental intestinal fibrosis in vitro and in vivo.
CONCLUSION
MFGE8 displays antifibrotic effects, and its administration may represent a future approach for prevention of IBD-induced intestinal strictures.
目的
肠纤维化被认为是慢性 IBD 的必然结果，导致狭窄形成和需要手术。在纤维化过程中，细胞外基质（ECM）成分对间充质细胞的功能起着关键作用。我们对纤维狭窄性克罗恩病（CD）和对照组织中的 ECM 组成和功能进行了特征描述。
设计
使用三种不同的方案对脱细胞全层肠组织平台进行了测试，并通过蛋白质组学探索了不同组织表型中的 ECM 组成，并通过定量 PCR（qPCR）和免疫组织化学进行了验证。用乳脂肪球表皮生长因子 8（MFGE8）处理原代人肠成纤维细胞（HIMFs），以评估其抗纤维化反应的机制，并在两种实验性肠道纤维化模型中测试 MFGE8 的作用。
结果
我们建立并验证了一种用于肠道 IBD 组织的优化脱细胞方案。基质组分析显示，CD 狭窄（CDs）组织中 MFGE8 的表达升高，在 mRNA 和蛋白水平上均得到证实。MFGE8 处理可抑制正常对照 HIMFs 的 ECM 产生，但不能抑制 CDs HIMFs 的 ECM 产生。下一代测序揭示了功能相关的整合素介导的信号通路，而整合素 αvβ5 和粘着斑激酶的阻断使 HIMFs 对 MFGE8 无反应。MFGE8 可预防和逆转体外和体内实验性肠道纤维化。
结论
MFGE8 具有抗纤维化作用，其给药可能代表预防 IBD 诱导的肠道狭窄的未来方法。
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