Dynamic Fibroblast Contractions Attract Remote Macrophages In Fibrillar Collagen Matrix
Pardis Pakshir1, Moien Alizadehgiashi2, Boaz Wong3, Nuno Miranda Coelho4, Christopher McCulloch5, Boris Hinz6.
1Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, toronto, ON, Canada, 2Department of Chemistry, University of Toronto, Toronto, ON, Canada, 3Department of Physiology, University of Western Ontario, London, ON, Canada, 4Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada, 5Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, TORONTO, ON, Canada, 6Laboratory of Tissue Repair and Regeneration, Matrix Dynamics Group, Faculty of Dentistry, University of Toronto, Toronto, ON, Canada.
Intimate communication between macrophages (Mϕ) and fibroblasts is important for tissue repair after injury and miscommunication can lead to pathological healing and fibrosis. The guidance cues and mechanisms directing migratory Mϕ towards collagen producing and contracting fibroblasts are unknown. We show that contracting fibroblasts generate deformation fields in fibrillar collagen matrix that provide far-reaching physical cues for Mϕ. When positioned within fibroblast deformation fields, Mϕ migrated towards the contraction source from distances of hundreds of micrometers. Mϕ chemotaxis was excluded by eliminating possible cytokine gradients with fluid flow and replacing fibroblasts with actuated microneedles as the force centre. Microneedle experiments identified the presence of a dynamic force source as the critical signal in the matrix to initiate and direct Mϕ migration. In contrast, collagen condensation and fiber alignment resulting from fibroblast remodelling activities were neither required nor sufficient to guide Mϕ migration. We propose a novel mechanism of far-ranging Mϕ mechanosensing that integrates locally sensed displacements of the substrate. We conclude that dynamic fibroblast contractile events are transmitted through fibrillar matrix and critical to attract Mϕ over distances that exceed the range of chemotactic gradients.
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