Macrophage‐Fibroblast Crosstalk Shapes Wound Repair Signaling In Vitro
Year: 2026
Type: article
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.
Source: The FASEB Journal
Institution: University of California, Irvine
Language: English
Topic: Wound Healing and Treatments
Subfield: Rehabilitation
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,740
Funders: California Institute for Regenerative Medicine, American Heart Association, Consejo Nacional de Ciencia y Tecnología, National Institutes of Health, National Heart, Lung, and Blood Institute, NIH Office of the Director, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: G2271690570, CIRM Scholars Comprehensive Research Training Program, G338893859, Biophysical regulation of macrophage function, G5139476368, G5805402537, Investigating the role of stiffness-mediated Piezo1 activity in foam cell formation, G681899484, Medical Scientist Training Program, Delivery of apoptotic neutrophils to improve angiogenesis during wound healing, Mechanochemical regulation of macrophages by the extracellular matrix during wound healing, Multiphoton Microscope for Cardiovascular and Tissue Engineering, G8639163658, Mechanical regulation of skin repair and regeneration
OpenAlex ID: W7161579991