Mechanistic insights and translational perspectives on liver fibrosis through single-cell transcriptomics.

Abstract

Liver fibrosis is a defining feature of chronic liver diseases and can progress to cirrhosis and liver failure. Single-cell RNA sequencing (scRNA-seq) enables high-resolution analysis of cellular heterogeneity and multicellular interactions during fibrogenesis. In this narrative review, we analyzed published single-cell transcriptomic studies from experimental models and human cohorts, focusing on cell-type-specific programs, cell-state trajectories inferred by Monocle, and intercellular communication networks predicted using CellChat and CellPhoneDB. Hepatic stellate cells (HSCs) consistently emerged as the primary extracellular matrix-producing cells, with conserved activation signatures involving collagen synthesis, Phosphatidylinositol 3-kinase-Protein kinase B (PI3K-AKT) signaling, and matrix organization. Macrophage analyses identified fibrosis-associated subsets, including CD9+ and TREM2+ scar-associated macrophages (SAMs), which regulate inflammation, angiogenesis, and stromal remodeling. Liver sinusoidal endothelial cells undergo capillarization and transcriptional reprogramming linked to WNT signaling and antigen presentation. B cells exhibit activation signatures related to B-cell receptor signaling. Trajectory analyses infer potential cell-state transitions based on transcriptional similarity from quiescent to pathogenic states, including stepwise HSC activation and monocyte-to-macrophage differentiation. Cell-cell communication analysis highlights HSC-macrophage interactions, with key axes such as predicted Chemokine ligand 2-chemokine receptor 2 (CCL2-CCR2) and transforming growth factor-β-transforming growth factor-β receptor (TGFβ-TGFβR) signaling interactions that may contribute to fibrogenic communication networks. These findings define conserved multicellular programs and support integrated multi-omics approaches for biomarker discovery and therapy.

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