Matrix viscoelasticity promotes cardiac fibroblast-macrophage fibrotic crosstalk

Here, we introduce a novel viscoelastic coculture platform that enables precise interrogation of mechanical and paracrine signaling in a physiologically relevant context. Counterintuitively, we found that soft, viscous environments promote human induced pluripotent stem cell-derived cardiac fibroblast activation and macrophage healing phenotypes, while stiff environments bias macrophages toward inflammation.

Coculture in soft, viscous matrices amplifies reciprocal pro-fibrotic signaling, and sequential exposure to inflammatory followed by healing activated macrophages, which recapitulate in vivo dynamics, further exacerbates fibroblast activation. Mechanistically, we identified a viscoelasticity-driven positive feedback loop involving inflammatory cytokines IL6, CCL5, and CCL2 as well as healing cytokines VEGFA and CTGF. This work establishes tissue viscoelasticity as a central regulator of immune–stromal interactions and provides a broadly applicable platform for dissecting mechanobiological drivers of fibrosis.