COX2+/PDGFRα+ fibroblasts selectively localize near bile ducts and interact with immune cells in early liver fibrosis in mice.

Liver fibrosis is a growing global health problem with no effective treatments. PDGFRα-positive fibroblasts are the main drivers of liver fibrosis, but their cellular heterogeneity is not fully understood. In this study, we performed single-cell RNA sequencing (scRNA-seq) on PDGFRα-positive fibroblasts isolated from healthy mouse livers. We also induced liver fibrosis via bile duct ligation (BDL) and examined their interactions with immune cells. scRNA-seq revealed that PDGFRα-positive fibroblasts mainly consist of hepatic stellate cells and portal fibroblasts. CellChat analysis indicated that a COX2-high (Ptgs2-high) subpopulation may preferentially interact with immune cells. This COX2-positive PDGFRα-positive fibroblast subset, also reported in other organs, localizes around bile ducts in the liver. Furthermore, when FACS-sorted PDGFRα-positive fibroblasts were treated with IL-1β in vitro, the proportion of COX2-positive cells increased. These findings demonstrate that PDGFRα-positive fibroblasts exhibit diversity in their responses to immune signals, with the COX2-positive subset potentially playing a key role in early fibrotic responses. Clarifying this heterogeneity may improve understanding of early liver fibrosis and support development of new therapeutic strategies.