Single-cell transcriptomics of hepatic stellate cells uncover crucial pathways and key regulators involved in non-alcoholic steatohepatitis.
Single-cell transcriptomics of hepatic stellate cells uncover crucial pathways and key regulators involved in non-alcoholic steatohepatitis.
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DOI：
10.1530/ec-22-0502
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发表时间：
2023-02-01
影响因子：
2.9
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
He W;Huang C;Shi X;Wu M;Li H;Liu Q;Zhang X;Zhao Y;Li X
纤维化是非酒精性脂肪性肝炎（NASH）发生发展的重要病理过程，而肝星状细胞（HSC）的激活是肝纤维化的核心事件。然而，NASH 患者中激活的 HSC (aHSC) 和静息 HSC (rHSC) 的转录组变化尚未得到评估。本研究旨在确定 NASH 发展过程中 HSC 的转录组特征及其潜在的关键功能途径。 HSC 的 NASH 相关转录组变化通过单细胞 RNA 测序 (scRNA-seq) 分析来定义，那些最上调的基因被鉴定为 NASH 相关转录组特征。通过加权基因共表达网络分析 (WGCNA) 和功能富集分析，探索了参与 aHSC 的 NASH 相关转录组变化的功能途径。通过上游调控因子分析和转录因子富集分析探索关键调控因子。 scRNA-seq 分析发现 NASH 患者和健康对照者之间的 rHSC 和 aHSC 中存在大量差异表达基因。 scRNA-seq分析和体内实验均显示正常肝脏中存在rHSC（主要表达a-SMA），而纤维化肝组织中aHSC（主要表达胶原1）增加。鉴定了 rHSC 的 NASH 相关转录组特征 (NASHrHSCsignature) 和 aHSC 的 NASH 相关转录组特征 (NASHaHSCsignature)。 WGCNA揭示了与aHSC转录组变化相关的主要途径。确定了 NASH 中 aHSC 功能变化的几个关键上游调节因子和转录因子。这项研究开发了一种有用的转录组学特征，有可能评估 NASH 发展过程中纤维化的严重程度。这项研究还确定了 NASH 发展过程中 HSC 激活的主要途径。
Fibrosis is an important pathological process in the development of non-alcoholic steatohepatitis (NASH), and the activation of hepatic stellate cell (HSC) is a central event in liver fibrosis. However, the transcriptomic change of activated HSCs (aHSCs) and resting HSCs (rHSCs) in NASH patients has not been assessed. This study aimed to identify transcriptomic signature of HSCs during the development of NASH and the underlying key functional pathways. NASH-associated transcriptomic change of HSCs was defined by single-cell RNA-sequencing (scRNA-seq) analysis, and those top upregulated genes were identified as NASH-associated transcriptomic signatures. Those functional pathways involved in the NASH-associated transcriptomic change of aHSCs were explored by weighted gene co-expression network analysis (WGCNA) and functional enrichment analyses. Key regulators were explored by upstream regulator analysis and transcription factor enrichment analysis. scRNA-seq analysis identified numerous differentially expressed genes in both rHSCs and aHSCs between NASH patients and healthy controls. Both scRNA-seq analysis and in-vivo experiments showed the existence of rHSCs (mainly expressing a-SMA) in the normal liver and the increased aHSCs (mainly expressing collagen 1) in the fibrosis liver tissues. NASH-associated transcriptomic signature of rHSC (NASHrHSCsignature) and NASH-associated transcriptomic signature of aHSC (NASHaHSCsignature) were identified. WGCNA revealed the main pathways correlated with the transcriptomic change of aHSCs. Several key upstream regulators and transcription factors for determining the functional change of aHSCs in NASH were identified. This study developed a useful transcriptomic signature with the potential in assessing fibrosis severity in the development of NASH. This study also identified the main pathways in the activation of HSCs during the development of NASH.