Modeling and targeting cell-extracellular matrix communication to revert tissue fibrosis

Skin fibrosis is a complex disorder characterized by the replacement of healthy tissue by pathological extracellular matrix (ECM). Despite its significant health burden, current treatments remain largely ineffective, leaving patients without efficient therapies. This gap is due to a limited understanding of how ECM cues and cells of the fibrotic niche co-evolve and interact over time to drive fibrosis. To address this, we will dissect how space- and time-dependent changes in ECM properties during fibrotic remodelling drive dysfunctional alterations in cell-matrix communication, thus promoting fibrosis progression. To tackle this, we propose a multidisciplinary approach merging patient samples, bioinspired hydrogels, human cells, 3D bioprinting, and high-content analysis of fibrosis at cellular, molecular and tissue levels. With this patient-centred approach, we will create a modular hydrogel library with tissue-specific and programmable properties to uncover the role of ECM cues in fibrosis. By harnessing these new insights, we will capitalize on bioprinting to create unique 3D models recreating the heterogeneity and cell dynamics in human skin fibrosis to unveil tractable targets for therapeutic purposes. Overall, this high-impact project addresses a major health challenge – identify drivers of fibrosis – leading to the development of innovative 3D models for discovering therapeutics that ultimately reverse fibrosis without disturbing tissue homeostasis.