Single-cell insights into hepatic fibroblasts and stellate cells: heterogeneity in matrix remodelling in development, health, and disease

Abstract Hepatic fibroblasts and hepatic stellate cells (HSCs) are dynamic regulators of liver development, homeostasis, and disease beyond structural roles. Advances in single-cell transcriptomics have provided new evidence on their heterogeneity, plasticity, and diverse functions across developmental and pathological contexts. This review synthesises contribution from single-cell and single-nuclei RNA sequencing studies to the understanding of the ontogeny, transcriptional diversity, and roles of hepatic stromal populations in foetal and adult liver. We highlight distinct fibroblast and HSC subpopulations identified across development and disease, characterised by extracellular matrix programmes and markers associated with shaping the hepatic microenvironment. We further examine their activation in chronic liver disease and reprogramming into cancer-associated fibroblasts in hepatobiliary cancers, and discuss how single-cell approaches are contributing to the re-evaluation of stromal plasticity by revealing cell-state transitions and informing in vitro modelling and targeted therapies.