Sepsis-induced changes in hepatic cell communication in mice: RNA-seq on purified cells

Sepsis, which affects 49 million people yearly, killing 11 million of them, involves activation of inflammation, as well as significant metabolic reprogramming. The liver is affected by these changes and is confronted with pathogens and is a key organ in restoring homeostasis. We addressed the question to what extent cell-cell communication between hepatic cell types is affected in sepsis, using the CLP model of sepsis in mice. We sorted the four major hepatic cell types, hepatocytes (HEPs), hepatic stellate cells (HSCs), liver sinusoidal endothelial cells (LSECs) and Kupffer cells (KCs) as well as non-KC CD45+ cells and performed bulk deep RNAseq. Cell-specific pathways were studied, and we focused on cell-cell interactions between the cell types. We found that HSCs, which in control (Sham) animals are not significantly communicative, in sepsis behave as the major signal-spreading cell type, primarily stimulated by LSECs. The impact of the HSC signals on the other cell types was investigated by NicheNet and reveals interesting new insights into the initiation of diverse hepatic responses in sepsis, such as pathogen clearance, ECM remodeling, chemotaxis and metabolic reprogramming. HSCs may therefore be considered as primary cells to targets in sepsis. Overall design: RNA-seq profiling of purified hepatocytes, liver sinusoidal endothelial cells, hapatic stellate cells, kupfer cells and infiltrating CD45+ cells from mice after CLP or Sham surgery