Unraveling the activation process and core driver genes of HSCs during cirrhosis by single-cell transcriptome.

Worldwide, cirrhosis is a common cause of death, manifesting itself as fibrosis of the liver tissue. When the liver is damaged, the liver produces fibrotic, proliferative myofibroblasts, which are formed by the differentiation of activated hepatic stellate cells. There are no effective antifibrotic treatment options. To deeply explore the activation process of hepatic stellate cells (HSCs) and to discover better therapeutic target genes, single-cell RNA sequencing data on 13 non-cirrhotic liver tissue samples and 10 cirrhotic liver tissue samples were analyzed. We identified activated HSCs from the mesenchymal cell population with high expression of ACTA2. By pseudo-time analysis, we found that the key genes for the differentiation of HSCs into myofibroblasts were C3, CCDC80, COL1A1, COL3A1, DCN, FBLN1, IGFBP3, MXRA5, SERPINE1, and MYH11. Then, we found that the main regulators of HSCs from inactive to activated state were NTF3, NTRK3, NTRK2, JAG1, NOTCH3, ESAM, and CD46 by cell-cell communication analysis. In addition, we found that the top2 hub genes of activated HSCs were CRIP1 and ACTA2. The experimental results show that the top2 hub genes were significantly overexpressed in cirrhotic samples. Our work dissected key intercellular regulators and core driver genes during hepatic stellate cell activation during cirrhosis through single-cell transcriptome data analysis, providing a research strategy to discover rational therapeutic targets for cirrhosis and some important information for gene targeting therapy.