Exploring Sex- Age- and Tissue-Dependent Mechanisms of Fibrosis

PROJECT OVERVIEW

Fibrotic disease is one of the biggest healthcare challenges of the modern era.  It can affect any organ and happens when normal tissue is replaced by dense connective tissue altering tissue organisation and affecting organ physiology.  Currently, there are no effective treatments. Fibrotic pathology is associated with an extremely poor prognosis and a low quality of life.  The cost to the UK economy, and economies worldwide, is huge.  One of the major obstacles to developing treatments for fibrotic disease is that early events that trigger tissue damage and connective tissue deposition are not well understood, nor is it known when and why this process becomes irreversible.  Work in our labs has sought to better understand lung fibrosis, a condition with particularly dismal prognosis and survival rates. 

Like all tissues, the lung responds to tissue damage by activating inflammatory pathways,  followed by repair.  In the lung two specialised cell types play a key role in repair; alveolar fibroblasts deposit new extracellular matrix (ECM) to replace damaged tissue, and closely neighbouring AT2 progenitor cells proliferate and differentiate into new epithelial cells that restore barrier function of the alveolar epithelium. Fibrosis happens when these responses become dysregulated; alveolar fibroblasts relentlessly lay down new ECM, creating a stiff and mechanically constrained tissue microenvironment, and AT2 cells lose their ability to regenerate and are lost from the lung.  Our new data identify protective mechanisms in healthy lungs that ensure well-controlled repair after injury.  Alveolar fibroblast-derived metabolites limit autonomous ECM deposition, and act in a paracrine manner to ensure AT2 cell survival and fitness. These protective mechanisms are lost in people with lung fibrosis, in particular in males, and as people get older.  Sex and ageing are amongst the biggest risk factors for developing this disease.  Our data therefore provide a potential explanation for why disease is more common in men than women, over the life course.  Our data also show that similar protective mechanisms are lost in other tissues that are prone to fibrotic disease, such as the skin and in the liver, but here different cellular players are implicated in mediating organ health.

This project will investigate: 1) how alveolar fibroblast-derived metabolites keep fibroblasts and AT2 cells healthy, 2) how parallel protective mechanisms operate in different organs, 3) what causes loss of these mechanisms in disease, and 4) whether intervention in these pathways is an effective means to prevent or reverse fibrosis. 

The benefits of this work could be game changing for people with fibrosis. To date, the field has largely searched for drug targets that can be used to treat fibrosis in all organs.  However, our work reveals how organs use tissue specific processes to respond to injury and repair damage.  As such tissue specific approaches to preventing uncontrolled repair are needed.  This information shifts the way we think about disease intervention and could open entirely new ways to treat fibrotic disease.

KEYWORDS

Fibrosis, metabolism, stromal immunology, sex-specific disease intervention, mechanobiology 

TRAINING OPPORTUNITIES

This project benefits from a supervisory team comprising experts in matrix biology, mechanobiology and stromal immunology, and world leading clinicians. The Kennedy Institute is a renowned research centre, located in the heart of the University of Oxford’s Old Road campus, housing fundamental and clinician scientists working on diverse aspects of immunology and inflammation. This project will combine state of the art spatial transcriptomics, cellular immunology, biophysics, and tissue biology; training will be provided in a range of in vivo disease models and patient cohort tissue analysis, alongside immunological, bioinformatic, structural and molecular biology techniques. Students will join a vibrant postgraduate community at the Kennedy, that provides extensive peer and pastoral support for the duration of the project. The PhD programme includes a core curriculum of lectures and bespoke training covering aspects of science, data analysis, patient engagement, science outreach, entrepreneurship and beyond.  Students will join group meetings from each of the labs of the supervisory team and have the opportunity to network with world leading investigators from all walks of science at Institute seminars, workshops and careers events.

KEY PUBLICATIONS

Buckley CD, Midwood KS. Tracing the origins of lung fibrosis.Nat Immunol. 2024 Sep;25(9):1517-1519. doi: 10.1038/s41590-024-01934-6

Mulholland EJ, et al. Epithelial GREMLIN1 disrupts intestinal epithelial-mesenchymal crosstalk to induce a wnt-dependent ectopic stem cell niche through stromal remodelling. Nat Commun. 2025 Jun 4;16(1):5167. doi: 10.1038/s41467-025-60364-6.

Thomas, T., et al. A longitudinal single-cell atlas of anti-tumour necrosis factor treatment in inflammatory bowel disease. Nat Immunol 25, 2152–2165 (2024). https://doi.org/10.1038/s41590-024-01994-8

Hallou A, He R, Simons BD, Dumitrascu B. A computational pipeline for spatial mechano-transcriptomics.Nat Methods. 2025 Apr;22(4):737-750. doi: 10.1038/s41592-025-02618-1

Yang, N., et al. Cellular mechano-environment regulates the mammary circadian clock. Nat Commun 8, 14287 (2017). https://doi.org/10.1038/ncomms14287 

THEMES

Translational science, tissue biology, inflammation, mechanobiology 

CONTACT INFORMATION OF ALL SUPERVISORS

kim.midwood@kennedy.ox.ac.uk

christopher.buckley@kennedy.ox.ac.uk

adrien.hallou@kennedy.ox.ac.uk

nan.yang@kennedy.ox.ac.uk