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Updated: Jul 2, 2025
Rat Model of Adhesive Capsulitis of the Shoulder
Published on: September 28, 2018
A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
Michael T H Ng1, Rowie Borst2, Hamez Gacaferi2
1University of Oxford, Oxford, UK. michael.ng@ndorms.ox.ac.uk.
Abstract:
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+ macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.
Insights
Frozen shoulder resolution involves specific macrophage and fibroblast interactions. These cells, identified through single-cell analysis, suggest a developmental basis for resolving fibrosis.
Area of Science:
- Immunology
- Fibrosis Research
- Cell Biology
Background:
- Frozen shoulder is a unique self-resolving fibrotic condition.
- Understanding its resolution mechanisms can inform treatments for other fibrotic diseases.
Purpose of the Study:
- To investigate the cellular and molecular mechanisms underlying frozen shoulder resolution.
- To identify cell populations and interactions involved in resolving inflammation and fibrosis.
Main Methods:
- Single-cell transcriptomic profiling of frozen shoulder capsule tissue.
- Micro-cultures of patient-derived cells to study cell-matrix interactions.
- Cross-tissue analysis comparing shoulder capsule to rheumatoid arthritis synovial tissue.
- Spatial analysis of human fetal shoulder tissue.
Main Results:
- Identified distinct macrophage populations (MERTKlowCD48+ and MERTK+LYVE1+MRC1+) in frozen shoulder tissue.
- Discovered integrin-mediated interactions between MERTK+ macrophages and pro-resolving DKK3+/POSTN+ fibroblasts.
- Found shared gene expression patterns between MERTK+ macrophages in frozen shoulder and rheumatoid arthritis remission.
- Observed analogous cell populations in fetal shoulder tissue, suggesting developmental origins.
Conclusions:
- MERTK+ macrophages and DKK3+/POSTN+ fibroblasts play a key role in frozen shoulder resolution.
- Cell-matrix interactions and crosstalk between these cells are crucial for resolving fibrosis.
- The mechanisms for fibrosis resolution are established during shoulder development.
- This research provides a basis for developing therapies to resolve persistent fibrotic diseases.
