β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis.
β-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis.
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DOI：
10.1016/j.jhep.2015.01.036
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发表时间：
2015-07
影响因子：
25.7
通讯作者：
Friedman, Scott L.
中科院分区：
文献类型：
--
作者：
Kocabayoglu, Peri;Lade, Abigale;Lee, Youngmin A.;Dragomir, Ana-Cristina;Sun, Xiaochen;Fiel, Maria Isabel;Thung, Swan;Aloman, Costica;Soriano, Philippe;Hoshida, Yujin;Friedman, Scott L.
β-PDGF受体（β-PDGFR）的快速诱导是肝星状细胞活化的核心特征，但其在体内的细胞影响尚未得到充分表征。我们使用具有不同β-PDGFR活性的遗传模型，探讨了β-PDGFR介导的通路激活对肝星状细胞在肝损伤、肝纤维化和肝癌变中的作用，并评估了其在人类肝硬化中的预后意义。在四氯化碳（CCl 4）或胆管结扎后，评估了星状细胞中β-PDGFR的缺失或组成性激活对纤维化的影响。在纤维化肝脏中的肝癌发生在单剂量的二乙基亚硝胺（DEN）之后，随后重复注射CCl 4。对表达或缺乏β-PDGFR的分离星状细胞进行全基因组表达谱分析，以确定失调途径并评估其与人类肝硬化预后基因特征的相关性。肝星状细胞中β-PDGFR的消耗减少了体内损伤和纤维化，而其自身激活加速了纤维化。然而，在DEN诱导的肿瘤前病灶的发展方面没有差异。基因组分析显示ERK、AKT和NF-kB通路以及先前在丙型肝炎病毒（HCV）相关肝硬化中作为星状细胞中β-PDGFR下游的186个基因预后特征的子集。在人类队列中，β-PDGFR特征与HCC的发展无关，但与HCV肝硬化的不良结局显著相关。β-PDGFR是体内肝损伤和纤维化的关键介质，并导致人类肝硬化的不良预后，但不是通过增加HCC的发展。
Rapid induction of β-PDGF receptor (β-PDGFR) is a core feature of hepatic stellate cell activation, but its cellular impact in vivo is not well characterized. We explored the contribution of β-PDGFR-mediated pathway activation to hepatic stellate cell responses in liver injury, fibrogenesis, and carcinogenesis in vivo using genetic models with divergent β-PDGFR activity, and assessed its prognostic implications in human cirrhosis. The impact of either loss or constitutive activation of β-PDGFR in stellate cells on fibrosis was assessed following carbon tetrachloride (CCl4) or bile duct ligation. Hepatocarcinogenesis in fibrotic liver was tracked after a single dose of diethylnitrosamine (DEN) followed by repeated injections of CCl4. Genome-wide expression profiling was performed from isolated stellate cells that expressed or lacked β-PDGFR to determine deregulated pathways and evaluate their association with prognostic gene signatures in human cirrhosis. Depletion of β-PDGFR in hepatic stellate cells decreased injury and fibrosis in vivo, while its auto-activation accelerated fibrosis. However, there was no difference in development of DEN-induced pre-neoplastic foci. Genomic profiling revealed ERK, AKT, and NF-kB pathways and a subset of a previously identified 186-gene prognostic signature in hepatitis C virus (HCV)-related cirrhosis as downstream of β-PDGFR in stellate cells. In the human cohort, the β-PDGFR signature was not associated with HCC development, but was significantly associated with a poorer outcome in HCV cirrhosis. β-PDGFR is a key mediator of hepatic injury and fibrogenesis in vivo and contributes to the poor prognosis of human cirrhosis, but not by increasing HCC development.
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影响因子：
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Olson, Lorin E.;Soriano, Philippe
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