Time-resolved single-cell transcriptomics reveals the landscape and dynamics of hepatic cells in sepsis-induced acute liver dysfunction

BACKGROUND & AIMS: Sepsis-induced acute liver dysfunction often occurs early in sepsis and can exacerbate the pathology by triggering multiple organ dysfunction and increasing lethality. Nevertheless, our understanding of the cellular heterogeneity and dynamic regulation of major nonparenchymal cell lineages remains unclear. METHODS: Here, single-cell RNA sequencing was used to profile multiple nonparenchymal cell subsets and dissect their crosstalk during sepsis-induced acute liver dysfunction in a clinically relevant polymicrobial sepsis model. The transcriptomes of major liver nonparenchymal cells from control and sepsis mice were analysed. The alterations in the endothelial cell and neutrophil subsets that were closely associated with acute liver dysfunction were validated using multiplex immunofluorescence staining. In addition, the therapeutic efficacy of inhibiting activating transcription factor 4 (ATF4) in sepsis and sepsis-induced acute liver dysfunction was explored. RESULTS: Our results present the dynamic transcriptomic landscape of major nonparenchymal cells at single-cell resolution. We observed significant alterations and heterogeneity in major hepatic nonparenchymal cell subsets during sepsis. Importantly, we identified endothelial cell (CD31(+)Sele(+)Glut1(+)) and neutrophil (Ly6G(+)Lta4h(+)Sort1(+)) subsets that were closely associated with acute liver dysfunction during sepsis progression. Furthermore, we found that ATF4 inhibition alleviated sepsis-induced acute liver dysfunction, prolonging the survival of septic mice. CONCLUSIONS: These results elucidate the potential mechanisms and subsequent therapeutic targets for the prevention and treatment of sepsis-induced acute liver dysfunction and other liver-related diseases. IMPACT AND IMPLICATIONS: Sepsis-induced acute liver dysfunction often occurs early in sepsis and can lead to the death of the patient. Nevertheless, the pathogenesis of sepsis-induced acute liver dysfunction is not yet clear. We identified the major cell types associated with acute liver dysfunction and explored their interactions during sepsis. In addition, we also found that ATF-4 inhibition could be invoked as a potential therapeutic for sepsis-induced acute liver dysfunction.