Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis
Mesothelin/mucin 16 signaling in activated portal fibroblasts regulates cholestatic liver fibrosis
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DOI：
10.1172/jci88845
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发表时间：
2017-04-03
影响因子：
15.9
通讯作者：
Kisseleva, Tatiana
中科院分区：
文献类型：
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作者：
Koyama, Yukinori;Wang, Ping;Kisseleva, Tatiana
胆汁淤积性肝纤维化是由胆道阻塞引起的，与表达 Thy-1、fibulin 2 和最近发现的标记物间皮素 (MSLN) 的门静脉成纤维细胞 (PF) 的早期激活有关。在这里，我们证明了活化的PF（aPF）和肌成纤维细胞在胆管结扎（BDL）诱导的肝纤维化的发病机制中发挥着关键作用。在 BDL 损伤的小鼠中，有条件地消融 MSLN+ aPF 可使肝纤维化减弱约 50%。在 MSLN 缺陷小鼠（Msln(-/-) 小鼠）或 MSLN 配体粘蛋白 16 缺陷小鼠（Muc16(-/-) 小鼠）中观察到类似的结果。体外分析表明，MSLN 通过破坏抑制性 Thy-1-TGF beta RI 复合物的形成来调节 WT PF 的 TGF-β 1 诱导激活。 MSLN 还促进 FGF 介导的 WT aPF 增殖。治疗性施用抗 MSLN 阻断抗体可减轻 WT 小鼠中 BDL 诱导的纤维化。胆汁淤积性肝纤维化患者的肝脏标本中 MSLN+ aPF/肌成纤维细胞的数量增加，表明 MSLN 可能是抗纤维化治疗的潜在靶点。
Cholestatic liver fibrosis is caused by obstruction of the biliary tract and is associated with early activation of portal fibroblasts (PFs) that express Thy-1, fibulin 2, and the recently identified marker mesothelin (MSLN). Here, we have demonstrated that activated PFs (aPFs) and myofibroblasts play a critical role in the pathogenesis of liver fibrosis induced by bile duct ligation (BDL). Conditional ablation of MSLN+ aPFs in BDL-injured mice attenuated liver fibrosis by approximately 50%. Similar results were observed in MSLN-deficient mice (Msln(-/-) mice) or mice deficient in the MSLN ligand mucin 16 (Muc16(-/-) mice). In vitro analysis revealed that MSLN regulates TGF-beta 1-inducible activation of WT PFs by disrupting the formation of an inhibitory Thy-1-TGF beta RI complex. MSLN also facilitated the FGF-mediated proliferation of WT aPFs. Therapeutic administration of anti-MSLN-blocking Abs attenuated BDL-induced fibrosis in WT mice. Liver specimens from patients with cholestatic liver fibrosis had increased numbers of MSLN+ aPFs/myofibroblasts, suggesting that MSLN may be a potential target for antifibrotic therapy.