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

作者：Gan Chen, Chao Ren, Yao Xiao, Yujing Wang, Ren-qi Yao, Quan Wang, Guoxing You, Mingzi Lu, Shaoduo Yan, Xiaoyong Zhang, Jun Zhang, Yong-ming Yao, Hong Zhou · 发表于：JHEP Reports · 年份：2023 · DOI：10.1016/j.jhepr.2023.100718 · 被引用次数：18 · 研究领域：Sepsis Diagnosis and Treatment、Immune Response and Inflammation、Single-cell and spatial transcriptomics

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: ) 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...