Cellular census of human fibrosis defines functionally distinct stromal cell types and states
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Published on: May 7, 2019
Thomas B Layton1, Lynn Williams1, Fiona McCann1
1The Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Abstract:
Fibrotic disorders are some of the most devastating and poorly treated conditions in developed nations, yet effective therapeutics are not identified for many of them. A major barrier for the identification of targets and successful clinical translation is a limited understanding of the human fibrotic microenvironment. Here, we construct a stromal cell atlas of human fibrosis at single cell resolution from patients with Dupuytren's disease, a localized fibrotic condition of the hand. A molecular taxonomy of the fibrotic milieu characterises functionally distinct stromal cell types and states, including a subset of immune regulatory ICAM1+ fibroblasts. In developing fibrosis, myofibroblasts exist along an activation continuum of phenotypically distinct populations. We also show that the tetraspanin CD82 regulates cell cycle progression and can be used as a cell surface marker of myofibroblasts. These findings have important implications for targeting core pathogenic drivers of human fibrosis.
Insights
Researchers mapped human fibrosis at single-cell resolution, identifying distinct stromal cell types and immune regulatory fibroblasts. This atlas reveals new therapeutic targets for fibrotic disorders like Dupuytren
Area of Science:
- Fibrosis research
- Single-cell genomics
- Human tissue pathology
Background:
- Fibrotic disorders are severe, poorly treated conditions with limited therapeutic options.
- Understanding the human fibrotic microenvironment is crucial for developing effective treatments.
- Current knowledge of cellular heterogeneity in human fibrosis is limited.
Purpose of the Study:
- To create a single-cell resolution atlas of the human fibrotic microenvironment.
- To molecularly characterize stromal cell populations in fibrosis.
- To identify novel therapeutic targets for fibrotic diseases.
Main Methods:
- Single-cell RNA sequencing of patient-derived fibrotic tissue (Dupuytren's disease).
- Bioinformatic analysis to construct a molecular taxonomy of stromal cells.
- Identification and characterization of distinct cell states and subpopulations.
Main Results:
- A comprehensive molecular taxonomy of fibrotic stromal cells was established.
- Identified a subset of immune regulatory ICAM1-positive fibroblasts.
- Revealed myofibroblasts exist on an activation continuum with distinct phenotypes.
- Demonstrated CD82 as a regulator of cell cycle and a myofibroblast marker.
Conclusions:
- The study provides unprecedented insight into the cellular complexity of human fibrosis.
- Identified specific cell populations and markers with potential for therapeutic intervention.
- Findings pave the way for targeting core pathogenic drivers in fibrotic disorders.
