Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis

Cell-cell communication via ligand-receptor signaling is a fundamental feature of complex organs. Despite this, the global landscape of intercellular signaling in mammalian liver has not been elucidated. Here we perform single-cell RNA sequencing on non-parenchymal cells isolated from healthy and NASH mouse livers. Secretome gene analysis revealed a highly connected network of intrahepatic signaling and disruption of vascular signaling in NASH. We uncovered the emergence of NASH-associated macrophages (NAMs), which are marked by high expression of triggering receptors expressed on myeloid cells 2 (Trem2), as a feature of mouse and human NASH that is linked to disease severity and highly responsive to pharmacological and dietary interventions. Finally, hepatic stellate cells (HSCs) serve as a hub of intrahepatic signaling via HSC-derived stellakines and their responsiveness to vasoactive hormones. These results provide unprecedented insights into the landscape of intercellular crosstalk and reprogramming of liver cells in health and disease. This work illustrates the heterogeneity of liver non-parenchymal cells (NPCs) and their reprogramming during NASH pathogenesis. Using single-cell RNA-sequencing analysis, the authors mapped the landscape of the intrahepatic ligand-receptor signaling network and revealed two fundamental aspects of HSC biology: stellakine secretion and contractile response to vasoactive hormones. Hepatic vascular dysfunction and emergence of Trem2+ NASH-associated macrophages (NAMs) are two conserved features of mouse and human NASH.