Human Liver Regeneration Is Characterized by the Coordinated Expression of Distinct MicroRNA Governing Cell Cycle Fate
Human Liver Regeneration Is Characterized by the Coordinated Expression of Distinct MicroRNA Governing Cell Cycle Fate
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DOI：
10.1111/ajt.12183
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发表时间：
2013-05-01
影响因子：
8.8
通讯作者：
Aluvihare, V. R.
中科院分区：
文献类型：
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作者：
Salehi, S.;Brereton, H. C.;Aluvihare, V. R.
在缺乏足够的代偿性再生的情况下，过度的肝损伤可导致急性肝功能衰竭(ALF)和死亡，而不进行紧急肝移植(LT)。辅助性肝移植在这种情况下产生令人满意的结果，自然肝再生维持长期生存的前景。由于动物模型只部分概括了人类肝脏再生，我们研究了在这种独特的LT环境中控制它的分子机制，作为人类肝脏再生的范例。我们展示了在再生过程中microRNA(MiRNA)表达的协调变化，这些变化推动了增殖、先天免疫和血管生成。相反，在相似的队列中，再生失败与不同的miRNA执行细胞周期抑制和DNA甲基化有关。MiRNA的表达与体外重复的成功或失败的再生有关，分别触发了促进细胞周期进入或抑制细胞周期的主要再生相关基因的表达。此外，抑制miRNA150、663和503的下调与成功再生相关，诱导细胞增殖，这是成功再生的关键决定因素。我们的数据表明，人的肝脏再生可能是由不同的miRNA协调的，这些miRNA控制着与再生相关的关键过程，包括肝细胞增殖。据我们所知，这是第一次描述与人类肝脏再生相关的分子过程。
In the absence of adequate compensatory regeneration, overwhelming liver damage can cause acute liver failure (ALF) and death without emergent liver transplantation (LT). Auxiliary LT produces satisfactory outcomes in this setting, with the prospect of native liver regeneration sustaining long-term survival. Since animal models only partially recapitulate human liver regeneration, we investigated the molecular mechanisms controlling it in this unique LT setting, as an exemplar of human liver regeneration. We demonstrate coordinated changes in expression of microRNA (miRNA) during regeneration that drive proliferation, innate immunity and angiogenesis. In contrast, failed regeneration in a similar cohort is associated with distinct miRNA enforcing cell cycle inhibition and DNA methylation. The miRNA expression associated with successful or failed regeneration when recapitulated in vitro, triggered expression of cardinal regeneration-linked genes promoting cell cycle entry or inhibition, respectively. Furthermore, inhibition of miRNA 150, 663 and 503, whose downregulation is associated with successful regeneration, induced cell proliferation which a key determinant of successful regeneration. Our data indicate that human liver regeneration may be orchestrated by distinct miRNA controlling key regeneration-linked processes including hepatocyte proliferation. To our knowledge this is the first characterization of molecular processes associated with human liver regeneration.