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Published on: April 3, 2017
Single-cell transcriptomes identifies characteristic features of mouse macrophages in liver Mallory-Denk bodies
Rong Zhang1, Bei Zhong2, Jiashan He2
1School of Basic Medical Sciences, Guangzhou Medical University, The Sixth Affiliated Hospital of Guangzhou Medical University, Qingyuan People's Hospital, Guangzhou, China; Clinical Laboratory, The First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou 510080, China.
Abstract:
Mallory-Denk bodies (MDBs) consist of intracellular aggregates of misfolded proteins in ballooned hepatocytes and serve as important markers of progression in certain liver diseases. Resident hepatic macrophage-mediated inflammation influences the development of chronic liver diseases and cancer. Here, the first systematic study of macrophages heterogeneity in mice was conducted to illustrate the pathogenesis of MDB formation using single-nucleus RNA sequencing (snRNA-seq). Furthermore, we provided transcriptional profiles of macrophages obtained from the fractionation of mouse liver tissues following chronic injury. We equally identified seven discrete macrophage subpopulations, each involved in specific cellular activated pathways such as basal metabolism, immune regulation, angiogenesis, and cell cycle regulation. Among these, a specific macrophage cluster (Cluster4), a subpopulation specifically expressing genes that regulate cell division and the cell cycle, was identified. Interestingly, we found that CCR2 was significantly induced in Cluster2, thereby inducing monocytes to migrate to macrophages to promote MDB pathogenesis. Thus, our study is the first to demonstrate the heterogeneity of macrophages associated with liver MDB formation in mice through single-cell resolution. This serves as the basis for further insights into the pathogenesis of liver MDB formation and molecular mechanisms of chronic liver disease progression.
Insights
This study reveals macrophage heterogeneity in liver MDB formation using single-nucleus RNA sequencing. Specific macrophage subpopulations drive Mallory-Denk body (MDB) pathogenesis in chronic liver disease.
Area of Science:
- Hepatology and Immunology
- Single-cell transcriptomics
- Liver disease pathogenesis
Background:
- Mallory-Denk bodies (MDBs) are intracellular protein aggregates in hepatocytes, indicating liver disease progression.
- Hepatic macrophages play a crucial role in liver inflammation, chronic liver disease, and cancer development.
Purpose of the Study:
- To systematically investigate macrophage heterogeneity in mouse models of MDB formation.
- To elucidate the role of distinct macrophage subpopulations in the pathogenesis of MDBs.
- To identify molecular mechanisms underlying MDB formation in chronic liver injury.
Main Methods:
- Single-nucleus RNA sequencing (snRNA-seq) of mouse liver tissues.
- Fractionation of mouse liver tissues to isolate macrophages.
- Transcriptional profiling of identified macrophage subpopulations.
Main Results:
- Identification of seven discrete macrophage subpopulations with distinct activated pathways.
- Discovery of a specific macrophage subpopulation (Cluster 4) involved in cell cycle regulation.
- Significant induction of CCR2 in Cluster 2, promoting monocyte migration and MDB pathogenesis.
Conclusions:
- This study provides the first single-cell resolution demonstration of macrophage heterogeneity in liver MDB formation in mice.
- The findings offer insights into the pathogenesis of MDB formation and chronic liver disease progression.
- Identified macrophage subpopulations and pathways provide targets for future therapeutic strategies.
