Transcriptomic Dissection of Hepatocyte Heterogeneity: Linking Ploidy, Zonation, and Stem/Progenitor Cell Characteristics
Transcriptomic Dissection of Hepatocyte Heterogeneity: Linking Ploidy, Zonation, and Stem/Progenitor Cell Characteristics
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DOI：
10.1016/j.jcmgh.2019.08.011
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发表时间：
2020-01-01
影响因子：
7.2
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
--
作者：
Katsuda, Takeshi;Hosaka, Kazunori;Ochiya, Takahiro
背景与目的：关于肝细胞多倍体的生物学意义存在长期争论。最近的研究提供了越来越多的证据表明，具有不同倍性状态的肝细胞以环境依赖性方式表现不同（例如，对肿瘤发生的易感性，损伤后的再生能力和体外增殖能力）。然而，他们的整体转录组差异在生理context.METHODS：通过使用微阵列转录组分析，我们研究了异质性的肝细胞群体具有不同的倍性状态。此外，通过使用单细胞定量逆转录聚合酶链反应（scPCR）分析，我们调查了2c和4c hepatocyte.RESULTS：基因芯片分析显示，细胞周期相关基因在8c hepatocyte中富集，这与已建立的概念，即多倍体形成通过细胞分裂失败。令人惊讶的是，与2c肝细胞位于门静脉周围区域的普遍共识相反，在我们的批量转录组和scPCR分析中，2c肝细胞始终显示出中心周围肝细胞富集的特征。此外，scPCR分析鉴定了2c肝细胞内共表达肝祖细胞标志物Axin2、Prom1和Lgr5的亚群，这意味着该亚群的潜在生物学相关性。这项研究为肝细胞异质性提供了新的见解，即2c肝细胞优先定位于中央周围区，2c肝细胞亚群在肝祖细胞标志物表达方面显示肝祖细胞样特征
BACKGROUND & AIMS: There is a long-standing debate regarding the biological significance of polyploidy in hepatocytes. Recent studies have provided increasing evidence that hepatocytes with different ploidy statuses behave differently in a context-dependent manner (eg, susceptibility to oncogenesis, regenerative ability after injury, and in vitro proliferative capacity). However, their overall transcriptomic differences in a physiological context is not known.METHODS: By using microarray transcriptome analysis, we investigated the heterogeneity of hepatocyte populations with different ploidy statuses. Moreover, by using single-cell quantitative reverse-transcription polymerase chain reaction (scPCR) analysis, we investigated the intrapopulational transcriptome heterogeneity of 2c and 4c hepatocytes.RESULTS: Microarray analysis showed that cell cycle-related genes were enriched in 8c hepatocytes, which is in line with the established notion that polyploidy is formed via cell division failure. Surprisingly, in contrast to the general consensus that 2c hepatocytes reside in the periportal region, in our bulk transcriptome and scPCR analyses, the 2c hepatocytes consistently showed pericentral hepatocyte-enriched characteristics. In addition, scPCR analysis identified a subpopulation within the 2c hepatocytes that co-express the liver progenitor cell markers Axin2, Prom1, and Lgr5, implying the potential biological relevance of this subpopulation.CONCLUSIONS: This study provides new insights into hepatocyte heterogeneity, namely 2c hepatocytes are preferentially localized to the pericentral region, and a subpopulation of 2c hepatocytes show liver progenitor cell-like features in terms of liver progenitor cell marker expression