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

Xuelian Xiong, H. Kuang, S. Ansari, Tongyu Liu, Jianke Gong, S. Wang, Xu Yun Zhao, Y. Ji, C. Li, L. Guo, Linkang Zhou, Zhimin Chen, P. Leon-Mimila, Meng Ting Chung, Katsuo Kurabayashi, Judy Opp, Francisco Campos-Pérez, Hugo Villamil-Ramírez, Samuel Canizales-Quinteros, Robert LyonsCarey N. Lumeng, Beiyan Zhou, Ling Qi, Adriana Huertas-Vazquez, Aldons J. Lusis, X. Z.Shawn Xu, Siming Li, Yonghao Yu, J. Z. Li, Jiandie D. Lin

Research output: Contribution to journalArticle

6 Citations (Scopus)

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. 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.

Original languageEnglish (US)
Pages (from-to)644-660.e5
JournalMolecular cell
Volume75
Issue number3
DOIs
StatePublished - Aug 8 2019

Fingerprint

Hepatic Stellate Cells
Liver
RNA Sequence Analysis
Genes
Myeloid Cells
Blood Vessels
Macrophages
Hormones
Ligands
Cell Communication
Cell Biology
Pharmacology
Health
Cellular Reprogramming

Keywords

  • HSC
  • Kupffer
  • liver
  • macrophage
  • NAFLD
  • NASH
  • NPC
  • scRNA-seq
  • secretome
  • single-cell
  • stellakine
  • Trem2

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis. / Xiong, Xuelian; Kuang, H.; Ansari, S.; Liu, Tongyu; Gong, Jianke; Wang, S.; Zhao, Xu Yun; Ji, Y.; Li, C.; Guo, L.; Zhou, Linkang; Chen, Zhimin; Leon-Mimila, P.; Chung, Meng Ting; Kurabayashi, Katsuo; Opp, Judy; Campos-Pérez, Francisco; Villamil-Ramírez, Hugo; Canizales-Quinteros, Samuel; Lyons, Robert; Lumeng, Carey N.; Zhou, Beiyan; Qi, Ling; Huertas-Vazquez, Adriana; Lusis, Aldons J.; Xu, X. Z.Shawn; Li, Siming; Yu, Yonghao; Li, J. Z.; Lin, Jiandie D.

In: Molecular cell, Vol. 75, No. 3, 08.08.2019, p. 644-660.e5.

Research output: Contribution to journalArticle

Xiong, X, Kuang, H, Ansari, S, Liu, T, Gong, J, Wang, S, Zhao, XY, Ji, Y, Li, C, Guo, L, Zhou, L, Chen, Z, Leon-Mimila, P, Chung, MT, Kurabayashi, K, Opp, J, Campos-Pérez, F, Villamil-Ramírez, H, Canizales-Quinteros, S, Lyons, R, Lumeng, CN, Zhou, B, Qi, L, Huertas-Vazquez, A, Lusis, AJ, Xu, XZS, Li, S, Yu, Y, Li, JZ & Lin, JD 2019, 'Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis', Molecular cell, vol. 75, no. 3, pp. 644-660.e5. https://doi.org/10.1016/j.molcel.2019.07.028
Xiong, Xuelian ; Kuang, H. ; Ansari, S. ; Liu, Tongyu ; Gong, Jianke ; Wang, S. ; Zhao, Xu Yun ; Ji, Y. ; Li, C. ; Guo, L. ; Zhou, Linkang ; Chen, Zhimin ; Leon-Mimila, P. ; Chung, Meng Ting ; Kurabayashi, Katsuo ; Opp, Judy ; Campos-Pérez, Francisco ; Villamil-Ramírez, Hugo ; Canizales-Quinteros, Samuel ; Lyons, Robert ; Lumeng, Carey N. ; Zhou, Beiyan ; Qi, Ling ; Huertas-Vazquez, Adriana ; Lusis, Aldons J. ; Xu, X. Z.Shawn ; Li, Siming ; Yu, Yonghao ; Li, J. Z. ; Lin, Jiandie D. / Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis. In: Molecular cell. 2019 ; Vol. 75, No. 3. pp. 644-660.e5.
@article{420aff04ceec48c9a77aee5fb45de7fa,
title = "Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis",
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. 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.",
keywords = "HSC, Kupffer, liver, macrophage, NAFLD, NASH, NPC, scRNA-seq, secretome, single-cell, stellakine, Trem2",
author = "Xuelian Xiong and H. Kuang and S. Ansari and Tongyu Liu and Jianke Gong and S. Wang and Zhao, {Xu Yun} and Y. Ji and C. Li and L. Guo and Linkang Zhou and Zhimin Chen and P. Leon-Mimila and Chung, {Meng Ting} and Katsuo Kurabayashi and Judy Opp and Francisco Campos-P{\'e}rez and Hugo Villamil-Ram{\'i}rez and Samuel Canizales-Quinteros and Robert Lyons and Lumeng, {Carey N.} and Beiyan Zhou and Ling Qi and Adriana Huertas-Vazquez and Lusis, {Aldons J.} and Xu, {X. Z.Shawn} and Siming Li and Yonghao Yu and Li, {J. Z.} and Lin, {Jiandie D.}",
year = "2019",
month = "8",
day = "8",
doi = "10.1016/j.molcel.2019.07.028",
language = "English (US)",
volume = "75",
pages = "644--660.e5",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "3",

}

TY - JOUR

T1 - Landscape of Intercellular Crosstalk in Healthy and NASH Liver Revealed by Single-Cell Secretome Gene Analysis

AU - Xiong, Xuelian

AU - Kuang, H.

AU - Ansari, S.

AU - Liu, Tongyu

AU - Gong, Jianke

AU - Wang, S.

AU - Zhao, Xu Yun

AU - Ji, Y.

AU - Li, C.

AU - Guo, L.

AU - Zhou, Linkang

AU - Chen, Zhimin

AU - Leon-Mimila, P.

AU - Chung, Meng Ting

AU - Kurabayashi, Katsuo

AU - Opp, Judy

AU - Campos-Pérez, Francisco

AU - Villamil-Ramírez, Hugo

AU - Canizales-Quinteros, Samuel

AU - Lyons, Robert

AU - Lumeng, Carey N.

AU - Zhou, Beiyan

AU - Qi, Ling

AU - Huertas-Vazquez, Adriana

AU - Lusis, Aldons J.

AU - Xu, X. Z.Shawn

AU - Li, Siming

AU - Yu, Yonghao

AU - Li, J. Z.

AU - Lin, Jiandie D.

PY - 2019/8/8

Y1 - 2019/8/8

N2 - 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.

AB - 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.

KW - HSC

KW - Kupffer

KW - liver

KW - macrophage

KW - NAFLD

KW - NASH

KW - NPC

KW - scRNA-seq

KW - secretome

KW - single-cell

KW - stellakine

KW - Trem2

UR - http://www.scopus.com/inward/record.url?scp=85069736714&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85069736714&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2019.07.028

DO - 10.1016/j.molcel.2019.07.028

M3 - Article

C2 - 31398325

AN - SCOPUS:85069736714

VL - 75

SP - 644-660.e5

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 3

ER -