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

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-Pérez; Hugo Villamil-Ramírez; Samuel Canizales-Quinteros; Robert Lyons; Carey N Lumeng; Beiyan Zhou; Ling Qi; Adriana Huertas-Vazquez; Aldons J Lusis; X Z Shawn Xu; Siming Li; Yonghao Yu; Jun Z Li; Jiandie D Lin

doi:10.1016/j.molcel.2019.07.028

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

Mol Cell. 2019 Aug 8;75(3):644-660.e5. doi: 10.1016/j.molcel.2019.07.028.

Authors

Xuelian Xiong¹, Henry Kuang², Sahar Ansari³, Tongyu Liu², Jianke Gong⁴, Shuai Wang⁵, Xu-Yun Zhao², Yewei Ji⁶, Chuan Li⁷, Liang Guo², Linkang Zhou², Zhimin Chen², Paola Leon-Mimila⁸, Meng Ting Chung⁹, Katsuo Kurabayashi⁹, Judy Opp¹⁰, Francisco Campos-Pérez¹¹, Hugo Villamil-Ramírez¹², Samuel Canizales-Quinteros¹², Robert Lyons¹⁰, Carey N Lumeng¹³, Beiyan Zhou⁷, Ling Qi⁶, Adriana Huertas-Vazquez⁸, Aldons J Lusis⁸, X Z Shawn Xu¹⁴, Siming Li², Yonghao Yu⁵, Jun Z Li³, Jiandie D Lin¹⁵

Affiliations

¹ Ministry of Education Key Laboratory of Metabolism and Molecular Medicine, Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China; Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
² Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
³ Department of Human Genetics, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
⁴ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA; International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, and Huazhong University of Science and Technology, Wuhan, Hubei, China.
⁵ Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
⁶ Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
⁷ Department of Immunology, School of Medicine, University of Connecticut, Farmington, CT 06030, USA.
⁸ Department of Medicine, Division of Cardiology, David Geffen School of Medicine, Los Angeles, CA, USA.
⁹ Department of Mechanical Engineering, University of Michigan, Ann Arbor, MI 48105, USA.
¹⁰ University of Michigan DNA Sequencing Core, University of Michigan, Ann Arbor, MI 48109, USA.
¹¹ Clínica Integral de Cirugía para la Obesidad y Enfermedades Metabólicas, Hospital General Dr. Rubén Lénero, Mexico City, Mexico.
¹² Facultad de Química, UNAM/Instituto Nacional de Medicina Genómica (INMEGEN), Unidad de Genómica de Poblaciones Aplicada a la Salud, Mexico City, Mexico.
¹³ Department of Pediatrics and Communicable Diseases, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
¹⁴ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Molecular and Integrative Physiology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA.
¹⁵ Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109, USA; Department of Cell & Developmental Biology, University of Michigan Medical Center, Ann Arbor, MI 48109, USA. Electronic address: jdlin@umich.edu.

Abstract

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.

Keywords: HSC; Kupffer; NAFLD; NASH; NPC; Trem2; liver; macrophage; scRNA-seq; secretome; single-cell; stellakine.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Communication / genetics*
Cellular Reprogramming / genetics
Disease Models, Animal
Hepatic Stellate Cells / metabolism
Hepatic Stellate Cells / pathology
Humans
Ligands
Liver / metabolism*
Liver / pathology
Macrophages / metabolism
Macrophages / pathology
Mice
Non-alcoholic Fatty Liver Disease / genetics*
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Sequence Analysis, RNA*
Signal Transduction / genetics
Single-Cell Analysis

Substances

Ligands

Abstract

Publication types

MeSH terms

Substances

Grants and funding