ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2026
Macrophage-Fibroblast Crosstalk Shapes Wound Repair Signaling In Vitro.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.
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Abstract
Wound healing requires coordinated interactions between macrophages and fibroblasts, yet how contact-dependent signaling integrates with paracrine pathways to regulate their reciprocal behavior is not well defined. Here, we investigated macrophage-fibroblast communication using complementary 2D and 3D in vitro wound healing models combined with live-cell calcium imaging and single-cell RNA sequencing (scRNA-seq). We show that bone marrow-derived macrophages (BMDMs) promote fibroblast scratch closure in a contact-dependent manner independent of connexins, whereas fibroblasts reciprocally regulate macrophage cytokine secretion through distinct mechanisms. Direct cell-cell contact with fibroblasts enhanced macrophage IL10 production via connexin 43 (Cx43)-dependent signaling, whereas TNFα secretion was suppressed through paracrine interactions. We further demonstrate that fibroblast-macrophage contact induces connexin-dependent intermittent calcium signals selectively in macrophages. ScRNA-seq revealed that wounding reshapes macrophage and fibroblast populations, uncovering dynamic regulation of cell adhesion molecules (CAMs) and intercellular signaling pathways. Together, these findings reveal the integration of contact-dependent calcium and connexin signaling with transcriptional remodeling to coordinate macrophage-fibroblast behavior during healing.
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