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

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.