Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells
Neuropilin-1 promotes cirrhosis of the rodent and human liver by enhancing PDGF/TGF-β signaling in hepatic stellate cells
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DOI：
10.1172/jci41203
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发表时间：
2010-07-01
影响因子：
15.9
通讯作者：
Shah, Vijay H.
中科院分区：
文献类型：
--
作者：
Cao, Sheng;Yaqoob, Usman;Shah, Vijay H.
PDGF依赖的肝星状细胞（HSC）募集是肝纤维化和伴随该过程的窦状血管变化的重要步骤。然而，调节PDGF信号传导的机制仍然不完全确定。在这里，我们发现在两个大鼠肝纤维化模型中，轴突导向分子神经纤毛蛋白-1（NRP-1）在活化的HSC中上调，表现出高度运动的肌成纤维细胞表型。此外，NRP-1与PDGF-受体β（PDGFR β）在损伤模型以及人和大鼠HSC细胞系中的HSC中共定位。在人HSC中，siRNA介导的NRP-1敲低减弱了PDGF诱导的趋化性，而NRP-1过表达增加了细胞运动性和TGF-β依赖的胶原蛋白产生。类似地，经遗传修饰以缺乏NRP-1的小鼠HSC响应于PDGF处理显示出降低的运动性。免疫沉淀和生物化学结合研究表明，NRP-1增加了PDGF对PDGFR β表达细胞的结合亲和力，并促进下游信号传导。NRP-1中和抗体改善了HSC的募集，阻断了肝损伤大鼠模型中的肝纤维化，并且还减弱了培养的肝内皮细胞中的VEGF反应。此外，在丙型肝炎和脂肪性肝炎引起的肝硬化的人类标本中观察到NRP-1过表达。这些研究揭示了NRP-1作为多种生长因子靶点的调节剂的作用，这些靶点调节肝纤维化和伴随它的血管变化，并且可能对各种其他器官系统和疾病状况中的肝硬化和肌成纤维细胞生物学具有广泛的影响。
PDGF-dependent hepatic stellate cell (HSC) recruitment is an essential step in liver fibrosis and the sinusoidal vascular changes that accompany this process. However, the mechanisms that regulate PDGF signaling remain incompletely defined. Here, we found that in two rat models of liver fibrosis, the axonal guidance molecule neuropilin-1 (NRP-1) was upregulated in activated HSCs, which exhibit the highly motile myofibroblast phenotype. Additionally, NRP-1 colocalized with PDGF-receptor beta (PDGFR beta) in HSCs both in the injury models and in human and rat HSC cell lines. In human HSCs, siRNA-mediated knockdown of NRP-1 attenuated PDGF-induced chemotaxis, while NRP-1 overexpression increased cell motility and TGF-beta-dependent collagen production. Similarly, mouse HSCs genetically modified to lack NRP-1 displayed reduced motility in response to PDGF treatment. Immunoprecipitation and biochemical binding studies revealed that NRP-1 increased PDGF binding affinity for PDGFR beta-expressing cells and promoted downstream signaling. An NRP-1 neutralizing Ab ameliorated recruitment of HSCs, blocked liver fibrosis in a rat model of liver injury, and also attenuated VEGF responses in cultured liver endothelial cells. In addition, NRP-1 overexpression was observed in human specimens of liver cirrhosis caused by both hepatitis C and steatohepatitis. These studies reveal a role for NRP-1 as a modulator of multiple growth factor targets that regulate liver fibrosis and the vascular changes that accompany it and may have broad implications for liver cirrhosis and myofibroblast biology in a variety of other organ systems and disease conditions.