Resolution versus persistence of fibrosis: The extracellular matrix decides

Project overview

Fibrotic diseases affect multiple organ systems, increasing global morbidity and mortality¹. Fibrosis is the final common pathway for a wide range of diseases affecting joint soft tissues including tendons, ligaments and synovial tissues^2,3. Most fibrotic joint diseases such as chronic tendinopathy, arthrofibrosis and arthritis are progressive and irreversible. One exception is frozen shoulder, a chronic inflammatory fibrotic disease localised to the ligaments comprising the shoulder joint capsule which is self-limiting over time. The unique biology of this under-investigated condition has the potential to unlock the cellular and molecular basis by which soft tissue inflammation resolves, persists or leads to fibrosis.

We studied tissues and cells isolated from patients with advanced-stage frozen shoulder to gain insights into the biological processes underpinning fibrosis resolution. We identified integrin mediated, cell-matrix interactions between resolving macrophages and fibroblasts reduce inflammation and promote remodelling of the extracellular matrix (ECM), providing a cellular basis underpinning disease resolution⁴. This project will identify if ECM niches surrounding populations of resolving and pro-inflammatory macrophages differ. The project will next compare these macrophage ECM niches in frozen shoulder patient tissues where fibrosis resolves, relative to tissues from patients with chronic tendinopathy, knee arthrofibrosis and rheumatoid arthritis where fibrosis persists. Analysis will involve working with existing scRNAseq datasets of the above patient tissues and spatial analysis of matrisomal postcodes in the context of the tissue microanatomy. Findings from this project will advance understanding of cell:matrix interactions regulating the resolution vs. persistence of fibrosis, informing new therapeutic targets to target and prevent these disabling musculoskeletal diseases. 

Training

The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. Training will be provided in techniques including scRNAseq, histology, multiplex immunohistochemistry, mass cytometry imaging, and flow cytometry.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome.  Students will also be required to attend regular seminars within the Department and those relevant in the wider University.

Students will be expected to present data regularly in Departmental seminars, the Dakin & Midwood Laboratory Group meetings and to attend external conferences to present their research globally, with limited financial support from the Department. 

Students will also have the opportunity to work closely with the Buckley & Coles collaborating Research Groups:

https://www.ndorms.ox.ac.uk/research/research-groups/stromal-cell-biology

https://www.ndorms.ox.ac.uk/research/research-groups/stromal-and-systems-immunology-group 

Students will have access to various courses run by the Medical Sciences Division Skills Training Team and other Departments. All students are required to attend a 2-day Statistical and Experimental Design course at NDORMS and run by the IT department (information will be provided once accepted to the programme). 

How to Apply

The Department accepts applications throughout the year but it is recommended that, in the first instance, you contact the relevant supervisor(s) or the Graduate Studies Office (graduate.studies@ndorms.ox.ac.uk) who will be able to advise you of the essential requirements.

Interested applicants should have, or expect to obtain, a first or upper second-class BSc degree or equivalent in a relevant subject and will also need to provide evidence of English language competence (where applicable).

The application guide and form is found online and the MSc (by Research) will commence in October 2025. Applications should be made to the following programme, using the specified course code:

MSc by Research in Molecular and Cellular Medicine (course code: RM_MP1)

For further information, please visit http://www.ox.ac.uk/admissions/graduate/applying-to-oxford.

References

1.         Thannickal, V.J., Zhou, Y., Gaggar, A. & Duncan, S.R. Fibrosis: ultimate and proximate causes. J Clin Invest 124, 4673-4677 (2014).

2.         Dakin SG, C.M., Sherlock J, Powrie F, Carr AJ, Buckley CD. Pathogenic stromal cells as therapeutic targets in joint inflammation. Nature reviews. Rheumatology (2018).

3.         Buckley, C.D., Ospelt, C., Gay, S. & Midwood, K.S. Location, location, location: how the tissue microenvironment affects inflammation in RA. Nature reviews. Rheumatology 17, 195-212 (2021).

4.         Ng, M.T.H., et al. A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution. Nature communications 15, 1394 (2024).

1. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4347226/pdf/JCI74368.pdf
2. https://www.nature.com/articles/s41584-018-0112-7
3. https://www.nature.com/articles/s41584-020-00570-2
4. https://www.nature.com/articles/s41467-024-45341-9

The Botnar Institute is a proud supporter of the Academic Futures scholarship programme, designed to address under-representation and help improve equality, diversity and inclusion in our graduate student body. The Botnar and the wider University rely on bringing the very best minds from across the world together, whatever their race, gender, religion or background to create new ideas, insights and innovations to change the world for the better. Up to 50 full awards are available across the three programme streams, and you can find further information on each stream on their individual tabs (Academic futures | Graduate access | University of Oxford).