Hepatic stellate cell heterogeneity: Functional aspects and therapeutic implications

Hepatic stellate cells (HSCs) represent a highly heterogeneous mesenchymal cell population with multifaceted roles in liver homeostasis and disease. Beyond their well-established roles in vitamin A storage and scar formation, there is increasing evidence for HSCs in the regulation of hepatic metabolism, regeneration, immunity, and carcinogenesis. Here, we will review the heterogeneity of HSCs in the healthy, aging, and diseased liver, focusing on cell-cell interactions and their contributions to fibrosis, liver zonation and function, regeneration, and cancer. We explore the spatiotemporal diversity of HSCs, highlighting their subpopulations and their specialized roles, as well as the complex bidirectional communications between HSCs, hepatocytes, endothelial cells (ECs), macrophages/monocytes, T cells, and tumor cells. By integrating insights from single-cell sequencing, spatial transcriptomics, preclinical data, and clinical data, this review aims to provide an updated understanding of how HSC heterogeneity contributes to liver homeostasis and disease and can be targeted for therapeutic purposes.