Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development.
Systems biological analyses reveal the hepatitis C virus (HCV)-specific regulation of hematopoietic development.
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系统生物学分析揭示了丙型肝炎病毒（HCV）对造血发育的特异性调节。
DOI：
10.1002/hep.27575
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发表时间：
2015
期刊：
影响因子：
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通讯作者：
Grakoui,Arash
中科院分区：
文献类型：
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作者：
Velazquez,VictoriaM;Uebelhoer,LukeS;Thapa,Manoj;Ibegbu,ChrisC;Courtney,Cynthia;Bosinger,StevenE;Magliocca,JosephF;Adams,AndrewB;Kirk,AllanD;Knechtle,StuartJ;Kalman,Daniel;Suthar,MehulS;Grakoui,Arash
慢性肝病的特征是肝脏富含髓样树突状细胞（DC）。为了评估疾病对骨髓生成的作用，我们利用系统生物学方法研究表达干细胞标志物CD 34的肝驻留细胞的发育。在终末期肝病患者中，肝脏CD 34+细胞由两个亚群组成，称为CD 34 + CD 146+和CD 34 + CD 146-，造血功能仅限于CD 34 + CD 146-细胞。与酒精性肝病（ALD）相比，非酒精性脂肪性肝炎（NASH）和慢性丙型肝炎病毒（HCV）期间肝脏CD 34频率降低，并且这种降低与HCV队列中的病毒载量相关。为了更好地了解肝脏CD 34 + CD 146+和CD 34 + CD 146-亚群之间的关系以及疾病对CD 34发展的任何影响，我们使用基因表达谱和计算模型来比较ALD和HCV期间的每个亚群。对于CD 34 + CD 146+细胞，与CD 34 + CD 146-细胞相比，观察到血管性血友病因子、VE-钙粘蛋白和deNOS等内皮细胞基因表达增加，并且观察到ALD和HCV疾病对基因表达的影响极小。重要的是，对于CD 34 + CD 146-细胞，慢性HCV与细胞周期、DNA修复、趋化性、发育和活化相关的程序的独特“印记”相关，重点是骨髓和B淋巴细胞谱系。这种HCV特征在并行分析中进一步转化，其中当相同培养时，与ALD和NASH相比，HCV CD 34 + CD 146-细胞表现出上级造血生长、集落形成和多样化。疾病对造血的相关影响也明显表现为髓系子代细胞表达CD 14、HLA-DR和CD 16的表型改变。肝脏可以是用于治疗的造血细胞的有用来源，或作为治疗靶点。（肝脏病学2015;61：843-856）
Chronic liver disease is characterized by the liver enrichment of myeloid dendritic cells (DCs). To assess the role of disease on myelopoiesis, we utilized a systems biology approach to study development in liver‐resident cells expressing stem cell marker CD34. In patients with endstage liver disease, liver CD34+ cells were comprised of two subsets, designated CD34+CD146+ and CD34+CD146–, and hematopoietic function was restricted to CD34+CD146– cells. Liver CD34 frequencies were reduced during nonalcoholic steatohepatitis (NASH) and chronic hepatitis C virus (HCV) compared to alcohol liver disease (ALD), and this reduction correlated with viral load in the HCV cohort. To better understand the relationship between liver CD34+CD146+ and CD34+CD146– subsets and any effects of disease on CD34 development, we used gene expression profiling and computational modeling to compare each subset during ALD and HCV. For CD34+CD146+ cells, increased expression of endothelial cell genes includingvon Willebrand factor, VE‐cadherin, andeNOSwere observed when compared to CD34+CD146– cells, and minimal effects of ALD and HCV diseases on gene expression were observed. Importantly for CD34+CD146– cells, chronic HCV was associated with a distinct “imprint” of programs related to cell cycle, DNA repair, chemotaxis, development, and activation, with an emphasis on myeloid and B lymphocyte lineages. This HCV signature was further translated in side‐by‐side analyses, where HCV CD34+CD146– cells demonstrated superior hematopoietic growth, colony formation, and diversification compared to ALD and NASH when cultured identically. Disease‐associated effects on hematopoiesis were also evident by phenotypic alterations in the expression of CD14, HLA‐DR, and CD16 by myeloid progeny cells.Conclusion: Etiology drives progenitor fate within diseased tissues. The liver may be a useful source of hematopoietic cells for therapy, or as therapeutic targets. (Hepatology2015;61:843–856)