Active Lungs & Breathing Digestion, Kidneys & Other Organs

Reversing pro-fibrotic fibroblast states through epigenetic modulation as a novel avenue to treat established intestinal fibrosis

Funder Wellcome Charity-funded
Recipient organisation University of Oxford
Funding £1.5M
Period Apr 2023 — Apr 2028

In plain English

AI plain-English summary

Surgeons remove scarred sections of intestine from Crohn’s disease patients because no drug can reverse the fibrosis that builds up in the gut wall. Current treatments for Crohn’s calm inflammation but do nothing about the stiff, fibrous tissue that forms in deeper intestinal layers. This leaves many patients facing repeated surgeries as the only option. The problem has been difficult to study because fibrotic lesions sit deep in the tissue and no good lab model has captured both the location and the mechanics of human small intestinal fibrosis. The researcher will use spatial profiling to examine full-thickness tissue from Crohn’s patients, identifying which fibroblasts drive scarring. A mouse model that closely mimics human Crohn’s fibrosis—driven by the PDGFRA pathway—will allow those pro-fibrotic cells to be targeted in living animals. Crucially, the researcher has already created an in vitro system that polarises intestinal fibroblasts into a disease-like state, and shown that this state can be reversed by epigenetic modulation. If the approach works in vivo, it could open a fundamentally new treatment avenue: reprogramming fibroblasts back to a normal state rather than simply blocking inflammation. This is fundamental science, but one with a clear path toward rational drug design.

View original technical description
Anti-inflammatory therapies do not stop or reverse fibrosis progression in Crohn’s disease (CD), leaving patients with the only remaining option of surgery. Research to reveal alternatives has been impeded by the unique tissue stiffness and location of fibrotic lesions in deeper layers of the intestine; and by the lack of in vivo models that would both recapitulate small intestinal fibrosis and allow mechanistic studies. I propose to use cutting- edge spatial profiling to study full-thickness CD patient tissues in situ. The platelet-derived growth factor alpha (PDGFRA) pathway drives small intestinal fibrosis in mice closely resembling CD fibrosis, and enables targeting of pro- fibrotic fibroblasts at the same time. In vivo disruption of the pro-fibrotic fibroblast pathways that we identify in CD patient tissues will enable studying the impact on fibrosis progression. I created an in vitro system to persistently polarise intestinal fibroblasts towards a phenotype that mirrors pathologic patient fibroblasts. Notably, this state is reversed by epigenetic modulation, representing a novel avenue for treating established fibrosis which will be explored in vitro and in vivo. By this, fundamental insights into fibroblast-driven mechanisms of intestinal fibrosis will be generated. This will enable rational drug design, including epigenetic fibroblast reprogramming.

View the original record at the funder ↗

Researchers

Matthias Friedrich (EPMC Awardee)

Related Research

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Validation of novel immunotherapeutic targets against fibrosis in inflammatory bowel diseases
Deconstructing the fibrotic microenvironment in Crohn's disease to promote tissue healing
Analysis of fibroblast modulation of leukocyte functions
Interrogating the cellular and molecular mechanisms of tissue fibrosis
Targeting fibroblasts in the treatment of inflammatory arthritis

Original classification

Career Development Award

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