Single-Cell Transcriptomics Uncovers Zonation of Function in the Mesenchyme during Liver Fibrosis

TLDR

Repeated liver injury drives progressive fibrosis that disrupts hepatic architecture, regeneration, and function, with hepatic stellate cells (HSCs) being the main source of pathological matrix yet traditionally viewed as a homogeneous population. The study aimed to use single‑cell RNA sequencing to dissect the hepatic mesenchyme in healthy and fibrotic mouse liver, uncovering spatial zonation of HSCs across the lobule. Single‑cell transcriptomic profiling of liver tissue from healthy and fibrotic mice was performed to resolve mesenchymal cell heterogeneity and spatial organization. We identified two spatially distinct HSC populations—portal vein‑associated and central vein‑associated—where the central vein‑associated cells are the primary collagen‑producing, pathogenic fibroblasts, and demonstrated that LPAR1 blockade on these cells reduces fibrosis in a rodent NASH model.

Abstract

Iterative liver injury results in progressive fibrosis disrupting hepatic architecture, regeneration potential, and liver function. Hepatic stellate cells (HSCs) are a major source of pathological matrix during fibrosis and are thought to be a functionally homogeneous population. Here, we use single-cell RNA sequencing to deconvolve the hepatic mesenchyme in healthy and fibrotic mouse liver, revealing spatial zonation of HSCs across the hepatic lobule. Furthermore, we show that HSCs partition into topographically diametric lobule regions, designated portal vein-associated HSCs (PaHSCs) and central vein-associated HSCs (CaHSCs). Importantly we uncover functional zonation, identifying CaHSCs as the dominant pathogenic collagen-producing cells in a mouse model of centrilobular fibrosis. Finally, we identify LPAR1 as a therapeutic target on collagen-producing CaHSCs, demonstrating that blockade of LPAR1 inhibits liver fibrosis in a rodent NASH model. Taken together, our work illustrates the power of single-cell transcriptomics to resolve the key collagen-producing cells driving liver fibrosis with high precision.