Organ-specific fibroblast dynamics revealed via an integrated experimental-computational framework
Fibrosis is a progressive pathological process driven by dysregulated fibroblast activity and excessive extracellular matrix deposition, leading to scarring, functional decline and eventually organ failure. Although fibroblasts are key mediators of fibrotic remodelling, it remains unclear whether their behaviours are conserved across tissues or organ specific. Here, we combine experimental and computational approaches to dissect fibroblast dynamics underlying cardiac and pulmonary fibrosis. Using in vitro assays, we demonstrate that cardiac and lung fibroblasts differ in morphology, proliferation, and collagen matrix organisation, likely reflecting tissue-specific mechanical and biochemical demands. Lung fibroblasts display higher proliferative capacity and increased myofibroblast activation, forming condition-dependent collagen architectures, with fibres that are more aligned under proinflammatory and fibrotic conditions, but less so under anti-inflammatory conditions. In contrast, cardiac fibroblasts consistently generate diffuse, isotropic collagen matrices across all cytokine conditions. Integrating these data into a mechanistic computational model of fibroblast-collagen interactions, we show that fibroblast motility, rather than cell-cell interactions, dominates tissue dynamics, and that coupling between motility and local collagen density regulates matrix architecture. Simulations reveal that collagen-dependent motility and density-dependent collagen secretion prevent maladaptive matrix alignment, identifying potential mechanisms restraining fibrotic progression. Our findings uncover organ-specific fibroblast behaviours and highlight how integrating experimental and computational frameworks can illuminate the dynamic rules governing fibrosis and inform targeted antifibrotic strategies.