Cirrhosis is widespread worldwide, is associated with the progression of chronic liver disease, and is a key link in leading to hepatocellular carcinoma. Cirrhosis remains a major global health challenge due to its insidious onset and lack of effective treatment options, and human intervention in the early stages of the disease is essential. At the 58th Annual Meeting of the European Society for the Study of the Liver (EASL2023) and the 2023 EASL Congress (EASL Congress 2023), the team of Professor Niu Junqi of Bethune First Hospital of Jilin University introduced the latest findings on the pathogenesis of liver fibrosis, providing bulk and single-cell RNA sequencing data of human hepatic stellate cells (HSCs) and potential biomarkers of liver cirrhosis [1]. Liver Disease International hereby reports.
At present, the exact mechanism of liver fibrosis is not fully clear, the huge medical demand for anti-fibrosis treatment has not been met, and the research of efficient and specific anti-fibrotic drugs has become a hot spot and difficulty in the field of liver disease. Hepatic stellate cells (HSCs) play a central role in cirrhosis, and understanding the signals and intracellular events that drive HSCs activation can help decipher the molecular mechanisms of liver fibrosis.
Based on animal experiments predicting that human diseases become complex due to species differences, most cell lines are tumor-like cells with long-term passage ability and do not reflect the true picture of the disease. Isolation of human primary cells to study liver fibrosis has clinical significance and practical value. Based on this, Professor Niu's team performed targeted bulk and single-cell transcriptomic analysis using patient-derived primary HSCs. Among them, bulk RNA sequencing was performed by two comparison protocols, protocol A: HSCs in 9 patients with cirrhosis versus HSCs in 6 patients with non-cirrhosis; Protocol B: 7 culture-activated HSCs versus 7 freshly isolated HSCs (paired analysis).
In bulk RNA sequencing, protocols A and B observed 3828 and 2262 differentially expressed genes, respectively, which could be significantly enriched into pathways such as "adhesion spots", "retinol metabolism" and "formation, assembly or degradation of collagen or ECM", and subsequent protein interaction analysis identified CAV1, ESR1, APP, SHC1, BCR, and LPL as key genes that may be interesting therapeutic targets. The upstream transcription factors were predicted by the KnockTF database, and POU5F1, ZFX, RARA, and MXD3 were considered to be important upstream transcription factors involved in the regulation of the differentially expressed genes in this study based on the transcription factor-differentially expressed gene network.
Single-cell sequencing included 4 cases of hepatitis B virus-associated cirrhosis and 3 cases of normal liver tissue, and cell populations characterized by high expression of DCN, ACTA2, COL1A1 and TAGLN were identified as myofibroblast-like HSCs. Quasi-time analysis showed that this population was located at the terminal end of the differentiation trajectory, regulated by hardening-associated endothelial cells, and passed through key ligand receptor pairs such as PDGFs-PDGFRs, ANGPTL4-SDC2/SDC4/ITGA5+ITGB1 and NAMPT-ITGA5+ITGB1. Pooling data found that 38 upregulated genes for myofibroblast-like HSCs in single-cell sequencing were shared in bulk RNA sequencing.
In general, the research of Professor Niu Junqi's team provided multiple sequencing data, revealed the change characteristics of human HSCs, explored the possible mechanism of liver fibrosis and potential diagnostic and therapeutic targets, and provided a theoretical basis for the clinical application of anti-fibrotic drugs. In the future, cell type-specific and target-specific drug interventions will make antifibrotic therapies more effective.
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Bibliography:
[1] Liu X, Ma H, Guan Q, et al. Bulk and single cell RNA sequencing profiling of human hepatic stellate cells and the potential biomarkers for liver cirrhosis. Journal of Hepatology 2023 vol. 78(S1) | S100–S1212. EASL 2023. Abstract WED-225.
First author
Liu Xu
Department of Hepatobiliary and Pancreatic Medicine, Bethune First Hospital, Jilin University, Ph.D
Leader of the national college student innovation project "Research on the Regulation of STAT5A by Trikocin A in Intervention in the Apoptosis of Gastric Cancer Cells"
Recipient of the National Scholarship for Doctoral Students
Excellent graduate student of Jilin University
He is committed to the research on the pathogenesis of liver cirrhosis and new strategies for diagnosis and treatment, and has published more than 10 SCI papers by the previous three authors
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Source: Editorial Board of International Journal of Liver Disease