Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration
Single-cell omics analysis reveals functional diversification of hepatocytes during liver regeneration
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DOI：
10.1172/jci.insight.141024
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发表时间：
2020-11-19
期刊：
影响因子：
8
通讯作者：
Diehl, Anna Mae
中科院分区：
文献类型：
--
作者：
Chen, Tianyi;Oh, Sehhoon;Diehl, Anna Mae
成人肝脏具有巨大的再生能力;它可以在失去三分之二的质量后再生，同时维持基本的代谢功能。肝脏如何平衡增加增殖活性与维持器官功能的双重需求尚不清楚，但对于预防肝衰竭至关重要。在小鼠中使用部分肝切除术（PHx）来模拟肝脏再生，我们整合了单细胞RNA和ATAC-Seq，以单细胞分辨率绘制了大约13，000个肝细胞中的状态转换，作为肝脏再生，并验证了IHC的关键发现，以揭示器官如何再生肝细胞，同时实现其重要的组织特异性功能。PHx后，肝细胞迅速和短暂地多样化成多个不同的群体，具有不同的功能分支：一些保留了未受损的成人肝脏中肝细胞的染色质景观和转录组，而另一些则过渡到获得胎肝细胞的染色质景观和转录组。已知对再生至关重要的损伤相关信号通路在过渡肝细胞中被激活，并且大多数胎儿样肝细胞表现出富含由这些通路调节的转录因子的染色质景观。
Adult liver has enormous regenerative capacity; it can regenerate after losing two-thirds of its mass while sustaining essential metabolic functions. How the liver balances dual demands for increased proliferative activity with maintenance of organ function is unknown but essential to prevent liver failure. Using partial hepatectomy (PHx) in mice to model liver regeneration, we integrated single-cell RNA- and ATAC-Seq to map state transitions in approximately 13,000 hepatocytes at single-cell resolution as livers regenerated, and validated key findings with IHC, to uncover how the organ regenerates hepatocytes while simultaneously fulfilling its vital tissue-specific functions. After PHx, hepatocytes rapidly and transiently diversified into multiple distinct populations with distinct functional bifurcation: some retained the chromatin landscapes and transcriptomes of hepatocytes in undamaged adult livers, whereas others transitioned to acquire chromatin landscapes and transcriptomes of fetal hepatocytes. Injury-related signaling pathways known to be critical for regeneration were activated in transitioning hepatocytes, and the most fetal-like hepatocytes exhibited chromatin landscapes that were enriched with transcription factors regulated by those pathways.