Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix

Abstract

Macrophage (Mϕ)-fibroblast interactions coordinate tissue repair after injury whereas miscommunications can result in pathological healing and fibrosis. We show that contracting fibroblasts generate deformation fields in fibrillar collagen matrix that provide far-reaching physical cues for Mϕ. Within collagen deformation fields created by fibroblasts or actuated microneedles, Mϕ migrate towards the force source from several hundreds of micrometers away. The presence of a dynamic force source in the matrix is critical to initiate and direct Mϕ migration. In contrast, collagen condensation and fiber alignment resulting from fibroblast remodelling activities or chemotactic signals are neither required nor sufficient to guide Mϕ migration. Binding of α2β1 integrin and stretch-activated channels mediate Mϕ migration and mechanosensing in fibrillar collagen ECM. We propose that Mϕ mechanosense the velocity of local displacements of their substrate, allowing contractile fibroblasts to attract Mϕ over distances that exceed the range of chemotactic gradients.

Regulation of nuclear architecture, mechanics, and nucleocytoplasmic shuttling of epigenetic factors by cell geometric constraints

“…We use the model to study fibroblasts cultured on fibronectin-coated micropatterned substrates. In our study, we focus on the stationary behavior of cells where cells have adopted the shape of the substrate while the model can be readily extended to study time-dependent behavior of cells as shown in our recent publications (37). All our experiments are also carried out in the stationary configuration where fibroblasts are fully constrained to the micropatterned substrate before and after drug treatment.…”

Autofluorescence imaging of 3D tumor-macrophage microscale cultures resolves spatial and temporal dynamics of macrophage metabolism

“…Monocultured macrophages exhibited minimal migration from the seeding plane, whereas co-cultured macrophages migrated further into the ECM toward the tumor layer especially at 24 and 48 hours ( Fig 5B&C). Therefore, the maximum migration distance for the monoculture condition was used to threshold passive from active macrophage migration at each time point (Fig 5B-D) 75 . Actively-migrating macrophages in co-culture have lower redox ratio at all time points, suggesting that these macrophages shift towards oxidative metabolism to enhance migration in the tumor microenvironment ( Fig 5E).…”

Diabetes alters the involvement of myofibroblasts during periodontal wound healing

“…Macrophages contribute with cytokines and growth factors necessary for wound healing (Klinkert et al, 2017). In addition, macrophage–fibroblast interactions are important during myofibroblast differentiation (Pakshir et al, 2019). Since diabetes may alter macrophage phenotype in diabetic wounds (Iacopino, 1995; Mirza et al, 2015), it is possible that dysfunctional macrophages may be associated with alterations in myofibroblast differentiation.…”