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

• DOI: 10.1016/j.molcel.2019.07.028
• Publication Date: 2019-08-08T14:43:10Z
• Authors: Xuelian Xiong; Henry Kuang; Sahar Ansari; Tongyu Liu; Jianke Gong; Shuai Wang; Xu-Yun Zhao; Yewei Ji; Chuan Li; Liang Guo; Linkang Zhou; Zhimin Chen; Paola Leon-Mimila; Meng Ting Chung; Katsuo Kurabayashi; Judy Opp; Francisco Campos-...; Hugo Villamil-Ram...; Samuel Canizales-...; Robert Lyons; Carey N. Lumeng; Beiyan Zhou; Ling Qi; Adriana Huertas-V...; Aldons J. Lusis; X.Z. Shawn Xu; Siming Li; Yonghao Yu; Jun Z. Li; Jiandie D. Lin
• Keywords: Crosstalk; Hepatic stellate cell; TREM2; Cell Signaling

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.