GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335271/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335271GEOGSEfalseMatrix viscoelasticity promotes cardiac fibroblast-macrophage fibrotic crosstalkCardiac fibrosis is driven by dynamic crosstalk between cardiac fibroblasts and macrophages, yet how tissue mechanics regulate these interactions remains poorly defined. 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.2026/09/02GSE335271GSM9809267GSM9809268GSM9809265GSM9809266GSM9809269GSM9809270GSM9809271GSM9809263GSM9809264GSM980926234284335271Homo sapiens