Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling.
Liver regeneration signature in hepatitis B virus (HBV)-associated acute liver failure identified by gene expression profiling.
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DOI：
10.1371/journal.pone.0049611
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Farci P
中科院分区：
文献类型：
--
作者：
Nissim O;Melis M;Diaz G;Kleiner DE;Tice A;Fantola G;Zamboni F;Mishra L;Farci P
肝脏通过成熟肝细胞的有丝分裂具有固有的再生能力，或者当肝脏损失严重或肝细胞增殖受损时，通过肝干/祖细胞（HSPC）的活化具有固有的再生能力。急性肝衰竭（ALF）的戏剧性临床过程对研究肝再生的分子机制和HSPC在这种情况下的作用构成了主要限制。我们研究了4例因B型肝炎病毒（HBV）相关ALF而接受肝移植的患者的肝再生的分子机制。来自4例ALF病例的17份肝脏标本和来自10名肝脏供体的个体标本的基因表达谱记录了ALF的独特基因特征。然而，无监督多维标度和分层聚类确定了两个ALF聚类，根据组织病理学严重程度大面积肝坏死（MHN; 2例患者）和亚大面积肝坏死（SHN; 2例患者）进行分离。我们发现ALF的特征是具有强烈的HSPC基因特征，沿着导管反应，这两者在MHN中更为突出。有趣的是，在MHN中没有观察到进一步谱系分化的证据，而在SHN中我们检测到具有肝细胞样形态的细胞。引人注目的是，ALF与一个强的肿瘤发生基因签名相关。MHN具有最大的干细胞基因（EpCAM，CK 19，CK 7）的上调，而SHN中上调最多的基因与细胞生长和增殖相关。肝坏死的程度与一个压倒性的纤维化基因特征相关，反映了伤口愈合过程。我们的数据为HBV相关ALF中一个独特的基因特征提供了证据，其强度与组织病理学严重程度直接相关。HSPC活化和纤维化与肝坏死程度呈正相关。此外，我们在ALF中检测到肿瘤发生基因签名，强调肝再生与肝癌之间的密切关系。
The liver has inherent regenerative capacity via mitotic division of mature hepatocytes or, when the hepatic loss is massive or hepatocyte proliferation is impaired, through activation of hepatic stem/progenitor cells (HSPC). The dramatic clinical course of acute liver failure (ALF) has posed major limitations to investigating the molecular mechanisms of liver regeneration and the role of HSPC in this setting. We investigated the molecular mechanisms of liver regeneration in 4 patients who underwent liver transplantation for hepatitis B virus (HBV)-associated ALF. Gene expression profiling of 17 liver specimens from the 4 ALF cases and individual specimens from 10 liver donors documented a distinct gene signature for ALF. However, unsupervised multidimensional scaling and hierarchical clustering identified two clusters of ALF that segregated according to histopathological severity massive hepatic necrosis (MHN; 2 patients) and submassive hepatic necrosis (SHN; 2 patients). We found that ALF is characterized by a strong HSPC gene signature, along with ductular reaction, both of which are more prominent in MHN. Interestingly, no evidence of further lineage differentiation was seen in MHN, whereas in SHN we detected cells with hepatocyte-like morphology. Strikingly, ALF was associated with a strong tumorigenesis gene signature. MHN had the greatest upregulation of stem cell genes (EpCAM, CK19, CK7), whereas the most up-regulated genes in SHN were related to cellular growth and proliferation. The extent of liver necrosis correlated with an overriding fibrogenesis gene signature, reflecting the wound-healing process. Our data provide evidence for a distinct gene signature in HBV-associated ALF whose intensity is directly correlated with the histopathological severity. HSPC activation and fibrogenesis positively correlated with the extent of liver necrosis. Moreover, we detected a tumorigenesis gene signature in ALF, emphasizing the close relationship between liver regeneration and liver cancer.
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影响因子：
13.5
作者：
Fausto, N;Campbell, JS;Riehle, KJ
通讯作者：
Riehle, KJ
影响因子：
82.9
作者：
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--
影响因子：
13.5
作者：
Mishra, Lopa;Banker, Tanuj;Murray, Joseph;Byers, Stephen;Thenappan, Arun;He, Aiwu Ruth;Shetty, Kirti;Johnson, Lynt;Reddy, E. P.
通讯作者：
Reddy, E. P.
影响因子：
7.5
作者：
Huang, CC;Chuang, JH;Tai, MH
通讯作者：
Tai, MH
影响因子：
2.3
作者：
Chiu, Chien-Chang;Sheu, Jin-Chuan;Lee, Hsuan-Shu
通讯作者：
Lee, Hsuan-Shu