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Reference-based analysis of lung single-cell sequencing reveals a transitional profibrotic macrophage. ​

Literature Information ​

DOI10.1038/s41590-018-0276-y
PMID30643263
JournalNature immunology
Impact Factor27.6
JCR QuartileQ1
Publication Year2019
Times Cited2393
Keywordssingle-cell RNA sequencing, lung fibrosis, transitional macrophages, pathological subgroup, fibrotic response
Literature TypeJournal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't
ISSN1529-2908
Pages163-172
Issue20(2)
AuthorsDvir Aran, Agnieszka P Looney, Leqian Liu, Esther Wu, Valerie Fong, Austin Hsu, Suzanna Chak, Ram P Naikawadi, Paul J Wolters, Adam R Abate, Atul J Butte, Mallar Bhattacharya

TL;DR ​

This study investigates the role of specific macrophage subgroups in tissue fibrosis using single-cell RNA sequencing in a bleomycin-induced lung fibrosis mouse model. The researchers identified a novel subgroup of CX3CR1+SiglecF+ transitional macrophages that are profibrotic and localized to the fibrotic niche, with their human gene homologs upregulated in idiopathic pulmonary fibrosis patients, highlighting their potential as therapeutic targets in fibrotic diseases.

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single-cell RNA sequencing · lung fibrosis · transitional macrophages · pathological subgroup · fibrotic response

Abstract ​

Tissue fibrosis is a major cause of mortality that results from the deposition of matrix proteins by an activated mesenchyme. Macrophages accumulate in fibrosis, but the role of specific subgroups in supporting fibrogenesis has not been investigated in vivo. Here, we used single-cell RNA sequencing (scRNA-seq) to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis in mice. A novel computational framework for the annotation of scRNA-seq by reference to bulk transcriptomes (SingleR) enabled the subclustering of macrophages and revealed a disease-associated subgroup with a transitional gene expression profile intermediate between monocyte-derived and alveolar macrophages. These CX3CR1+SiglecF+ transitional macrophages localized to the fibrotic niche and had a profibrotic effect in vivo. Human orthologs of genes expressed by the transitional macrophages were upregulated in samples from patients with idiopathic pulmonary fibrosis. Thus, we have identified a pathological subgroup of transitional macrophages that are required for the fibrotic response to injury.

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Primary Questions Addressed ​

  1. What specific mechanisms do transitional profibrotic macrophages employ to contribute to lung fibrosis?
  2. How does the presence of CX3CR1+SiglecF+ transitional macrophages influence the progression of idiopathic pulmonary fibrosis in humans?
  3. What other subgroups of macrophages might play a role in fibrogenesis, and how do they compare to the transitional macrophages identified in this study?
  4. How can the findings regarding transitional macrophages inform potential therapeutic strategies for treating lung fibrosis?
  5. What implications do the gene expression profiles of transitional macrophages have for understanding the broader context of immune responses in fibrotic diseases?

Key Findings ​

Research Background and Objectives ​

Lung fibrosis, particularly idiopathic pulmonary fibrosis (IPF), is a significant cause of mortality characterized by the deposition of extracellular matrix proteins by activated fibroblasts. While macrophages are known to accumulate in fibrotic tissues, their specific roles and subpopulations involved in fibrogenesis remain poorly understood. This study aims to characterize the heterogeneity of macrophages in bleomycin-induced lung fibrosis using single-cell RNA sequencing (scRNA-seq) and to identify a novel transitional profibrotic macrophage subgroup.

Main Methods/Materials/Experimental Design ​

The researchers employed single-cell RNA sequencing to analyze macrophage populations in the lungs of mice subjected to bleomycin-induced fibrosis. They developed a computational framework called SingleR for unbiased annotation of scRNA-seq data by comparing single-cell transcriptomes to reference bulk transcriptomes.

Experimental Workflow ​

Mermaid diagram
  1. Single-Cell Isolation: Lung tissues from bleomycin-treated and control mice were dissociated into single-cell suspensions.
  2. Single-Cell RNA Sequencing: scRNA-seq was performed using Drop-seq technology.
  3. SingleR Annotation: SingleR was used to annotate the cell types based on reference datasets, improving cell type identification.
  4. Hierarchical Clustering: Clustering analysis revealed three macrophage subclusters (C1, C2, C3).
  5. Functional Analysis: The transitional macrophage's role in fibrogenesis was investigated through functional assays.
  6. In Vivo and In Vitro Validation: Various experiments validated the findings, including fibroblast co-culture assays and immunofluorescence studies.

Key Results and Findings ​

  • Identification of Transitional Macrophages: SingleR identified a transitional macrophage subgroup (C2) that exhibited a gene expression profile intermediate between monocyte-derived and alveolar macrophages.
  • Localization and Function: These CX3CR1+SiglecF+ transitional macrophages localized to fibrotic niches and were found to produce PDGF-AA, a key mitogen for fibroblast proliferation.
  • Clinical Relevance: Human orthologues of genes expressed by transitional macrophages were upregulated in lung samples from patients with IPF, indicating a potential pathological role in human disease.

Main Conclusions/Significance/Innovation ​

This study uncovers a novel subgroup of transitional macrophages that are critical for the fibrotic response in lung injury. The findings suggest that these macrophages play a pivotal role in mediating the interaction between immune cells and fibroblasts, contributing to tissue fibrosis. The identification of specific markers such as CX3CR1 and PDGF-AA opens avenues for targeted therapies in fibrotic diseases.

Research Limitations and Future Directions ​

  • Specificity of Macrophage Markers: The study's reliance on CX3CR1 as a marker limits the specificity, as it is expressed in multiple macrophage populations.
  • Temporal Dynamics: Future research should focus on the kinetics of macrophage transitions over time to better understand their roles in fibrosis.
  • Broader Applications: The SingleR annotation method could be applied to other contexts to explore cellular heterogeneity in various diseases.

Summary Table of Key Findings ​

AspectFindings
Transitional MacrophagesIdentified as CX3CR1+SiglecF+ in fibrotic niches
MechanismProduce PDGF-AA, promoting fibroblast proliferation
Clinical CorrelationGene expression patterns relevant in human IPF samples
Research MethodologySingle-cell RNA sequencing with SingleR annotation

This comprehensive analysis enhances the understanding of macrophage roles in lung fibrosis and provides a foundation for future therapeutic strategies targeting these immune cells.

References ​

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Literatures Citing This Work ​

  1. Defining the Cell Types That Drive Idiopathic Pulmonary Fibrosis Using Single-Cell RNA Sequencing. - Joanna M Poczobutt;Oliver Eickelberg - American journal of respiratory and critical care medicine (2019)
  2. Single-Cell Profiling of Cutaneous T-Cell Lymphoma Reveals Underlying Heterogeneity Associated with Disease Progression. - Nicholas Borcherding;Andrew P Voigt;Vincent Liu;Brian K Link;Weizhou Zhang;Ali Jabbari - Clinical cancer research : an official journal of the American Association for Cancer Research (2019)
  3. Dissecting Cellular Heterogeneity Using Single-Cell RNA Sequencing. - Yoon Ha Choi;Jong Kyoung Kim - Molecules and cells (2019)
  4. Single-Cell RNA Profiling of Glomerular Cells Shows Dynamic Changes in Experimental Diabetic Kidney Disease. - Jia Fu;Kemal M Akat;Zeguo Sun;Weijia Zhang;Detlef Schlondorff;Zhihong Liu;Thomas Tuschl;Kyung Lee;John Cijiang He - Journal of the American Society of Nephrology : JASN (2019)
  5. Epithelial Expression of an Interstitial Lung Disease-Associated Mutation in Surfactant Protein-C Modulates Recruitment and Activation of Key Myeloid Cell Populations in Mice. - Alessandro Venosa;Jeremy Katzen;Yaniv Tomer;Meghan Kopp;Sarita Jamil;Scott J Russo;Surafel Mulugeta;Michael F Beers - Journal of immunology (Baltimore, Md. : 1950) (2019)
  6. The immunopathology of lung fibrosis: amphiregulin-producing pathogenic memory T helper-2 cells control the airway fibrotic responses by inducing eosinophils to secrete osteopontin. - Kiyoshi Hirahara;Ami Aoki;Yuki Morimoto;Masahiro Kiuchi;Mikiko Okano;Toshinori Nakayama - Seminars in immunopathology (2019)
  7. scMatch: a single-cell gene expression profile annotation tool using reference datasets. - Rui Hou;Elena Denisenko;Alistair R R Forrest - Bioinformatics (Oxford, England) (2019)
  8. Mast Cells, Angiogenesis and Lymphangiogenesis in Human Gastric Cancer. - Giuseppe Sammarco;Gilda Varricchi;Valentina Ferraro;Michele Ammendola;Michele De Fazio;Donato Francesco Altomare;Maria Luposella;Lorenza Maltese;Giuseppe Currò;Gianni Marone;Girolamo Ranieri;Riccardo Memeo - International journal of molecular sciences (2019)
  9. The role of macrophages in the resolution of inflammation. - Satoshi Watanabe;Michael Alexander;Alexander V Misharin;G R Scott Budinger - The Journal of clinical investigation (2019)
  10. Dissecting lung development and fibrosis at single-cell resolution. - Donna L Farber;Peter A Sims - Genome medicine (2019)

... (2383 more literatures)

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