Single-cell RNA transcriptome landscape of hepatocytes and non-parenchymal cells in healthy and NAFLD mouse liver

Summary Nonalcoholic fatty liver disease (NAFLD) is a global health care problem with limited therapeutic options. To obtain a cellular resolution of pathogenesis, 82,168 single cell transcriptomes (scRNAseq) across different NAFLD stages were profiled, identifying hepatocytes and 12 other non-parenchymal cell (NPC) types. scRNAseq revealed insights into the cellular and molecular mechanisms of the disease. We discovered a dual role for hepatic stellate cells in gene-expression regulation and in the potential to trans-differentiate into myofibroblasts. We uncovered distinct expression profiles of Kupffer cells versus monocyte-derived macrophages during NAFLD progression. Kupffer cells showed stronger immune responses, while monocyte-derived macrophages demonstrated a capability for differentiation. Three chimeric NPCs were identified including endothelial-chimeric stellate cells, hepatocyte-chimeric endothelial cells and endothelial-chimeric Kupffer cells. Our work identified unanticipated aspects of mouse NAFLD at the single-cell level and advanced the understanding of cellular heterogeneity in NAFLD livers.