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

Xiong, Xuelian; Kuang, Henry; Ansari, Sahar; Liu, Tongyu; Gong, Jianke; Wang, Shuai; Zhao, Xu-Yun; Ji, Yewei; Li, Chuan; Guo, Liang; Zhou, Linkang; Chen, Zhimin; León-Mimila, Paola; Chung, Meng Ting; Kurabayashi, Katsuo; Opp, Judy S.; Campos-Pérez, Francisco; Villamil‐Ramírez, Hugo; Canizales‐Quinteros, Samuel; Lyons, Robert H.; Lumeng, Carey N.; Zhou, Beiyan; Ling, Qi; Huertas‐Vazquez, Adriana; Lusis, Aldons J.; Xu, Xiaocai; Li, Siming; Yu, Yonghao; Li, Jun Z.; Lin, Jiandie D.

doi:10.1016/j.molcel.2019.07.028

Cited by 500 publications

(646 citation statements)

References 61 publications

(76 reference statements)

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“…Similar molecular signatures of LSEC zonation were observed in independent scRNA‐seq studies on NPCs isolated from healthy and NASH mouse liver and in human liver . Comparative analysis of LSEC transcriptomes obtained from healthy and NASH livers revealed profound defects in endothelial gene expression and vascular signaling that may contribute to disease pathogenesis . These studies provided an important first step in unraveling the molecular and functional heterogeneity of liver endothelial cells.…”

Section: Liver Cell Heterogeneity and Zonation At Single‐cell Resolutionsupporting

confidence: 67%

“…By taking advantage of the knowledge on zonated hepatocyte transcriptomes, Halpern et al developed a paired‐cell sequencing approach to probe heterogeneity of liver endothelial cells and bioinformatically inferred their spatial information . Similar molecular signatures of LSEC zonation were observed in independent scRNA‐seq studies on NPCs isolated from healthy and NASH mouse liver and in human liver . Comparative analysis of LSEC transcriptomes obtained from healthy and NASH livers revealed profound defects in endothelial gene expression and vascular signaling that may contribute to disease pathogenesis .…”

Section: Liver Cell Heterogeneity and Zonation At Single‐cell Resolutionmentioning

confidence: 89%

“…Despite the expanding role of intercellular signaling in metabolic physiology and tissue homeostasis, a comprehensive survey of ligand and receptor gene expression and the landscape of intercellular crosstalk in the liver have not been fully elucidated. Xiong et al performed single‐cell secretome gene analysis on NPCs and hepatocytes isolated from mouse liver . The secretome gene set includes those predicted to encode secreted factors (1,272) and membrane receptors (755) in the mouse genome .…”

Section: Landscape Of Intercellular Crosstalk Among Liver Cell Typesmentioning

confidence: 99%

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A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

et al. 2020

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Section: Liver Cell Heterogeneity and Zonation At Single‐cell Resolutionsupporting

confidence: 67%

Section: Liver Cell Heterogeneity and Zonation At Single‐cell Resolutionmentioning

confidence: 89%

Section: Landscape Of Intercellular Crosstalk Among Liver Cell Typesmentioning

confidence: 99%

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A Single‐Cell Perspective of the Mammalian Liver in Health and Disease

et al. 2020

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“…We recently performed single‐cell RNA‐seq (scRNA‐seq) analysis of liver cells in healthy and diet‐induced NASH mice . This scRNA‐seq data set contains gene expression data for hepatocytes and nonparenchymal cells at the single‐cell resolution.…”

Section: Resultsmentioning

confidence: 99%

hnRNPU/TrkB Defines a Chromatin Accessibility Checkpoint for Liver Injury and Nonalcoholic Steatohepatitis Pathogenesis

et al. 2020

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Background and Aims Nonalcoholic steatohepatitis (NASH) is a progressive liver disease that is characterized by liver injury, inflammation, and fibrosis. NASH pathogenesis is linked to reprogramming of chromatin landscape in the liver that predisposes hepatocytes to stress‐induced tissue injury. However, the molecular nature of the putative checkpoint that maintains chromatin architecture and preserves hepatocyte health remains elusive. Approach and Results Here we show that heterogeneous nuclear ribonucleoprotein U (hnRNPU), a nuclear matrix protein that governs chromatin architecture and gene transcription, is a critical factor that couples chromatin disruption to NASH pathogenesis. RNA‐seq and chromatin immunoprecipitation‐seq studies revealed an extensive overlap between hnRNPU occupancy and altered gene expression during NASH. Hepatocyte‐specific inactivation of hnRNPU disrupted liver chromatin accessibility, activated molecular signature of NASH, and sensitized mice to diet‐induced NASH pathogenesis. Mechanistically, hnRNPU deficiency stimulated the expression of a truncated isoform of TrkB (TRKB‐T1) that promotes inflammatory signaling in hepatocytes and stress‐induced cell death. Brain‐derived neurotrophic factor treatment reduced membrane TRKB‐T1 protein and protected mice from diet‐induced NASH. Conclusions These findings illustrate a mechanism through which disruptions of chromatin architecture drive the emergence of disease‐specific signaling patterns that promote liver injury and exacerbate NASH pathogenesis.

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“…Advances in single‐cell sequencing technology have facilitated the precise study of gene expression patterns in the mouse liver, revealing a previously unknown degree of heterogeneity within hepatocyte, cholangiocyte, endothelial cell, and immune cell compartments. Yet, translating lessons learned from the mouse liver to the human liver remains difficult, a situation underscored by the increasing incidence of liver disease in the United States and exacerbated by our limited understanding of the cellular composition of the human liver.…”

mentioning

confidence: 99%