Expansion of macrophage and liver sinusoidal endothelial cell subpopulations during non-alcoholic steatohepatitis progression

Liver non-parenchymal cells (NPCs) play a critical role in the progression of non-alcoholic steatohepatitis (NASH). We aimed to explore the heterogeneity of NPCs and identify NASH-specific subpopulations contributing to NASH progression. Through single-cell RNA sequencing, we uncovered a proinflammatory subpopulation of Itgad(hi)/Fcrl5(hi) macrophages with potential function of modulating macrophage accumulation and promoting NASH development. We also identified subpopulations of Egr1(hi) and Ly6a(hi) liver sinusoidal endothelial cells (LSECs), which might participate in pathological angiogenesis and inflammation regulation. The Itgad(hi)/Fcrl5(hi) macrophages, Egr1(hi) LSECs, and Ly6a(hi) LSECs emerged in the early stage and expanded significantly along with pathological progression of liver injury during NASH. Cell-cell interactions between hepatic stellate cells (HSCs) and Itgad(hi)/Fcrl5(hi) macrophages, Egr1(hi) LSECs or Ly6a(hi) LSECs were enhanced in NASH liver. Our results revealed that expansion of Itgad(hi)/Fcrl5(hi) macrophages, Egr1(hi) LSECs or Ly6a(hi) LSECs was strongly associated with NASH severity, suggesting these subpopulations might be involved in NASH progression.