Dynamic fibroblast contractions attract remote macrophages in fibrillar collagen matrix

Pardis Pakshir,Boris Hinz,Vivek B Shenoy,Moien Alizadehgiashi,Christopher A Mcculloch,Ze Gong,Boaz Wong,Nuno Miranda Coelho,Xingyu Chen

doi:10.1038/s41467-019-09709-6

Pardis Pakshir, Boris Hinz + Show 7 more

Open Access

https://doi.org/10.1038/s41467-019-09709-6

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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.

Highlights

We demonstrate that local remodeling of collagen fibers by contracting MFs provides far-ranging mechanical cues in the extracellular matrix (ECM) that attract and guide Mφ over long distances
Fibroblast contractions are sensed by other fibroblasts in the same fibrillar ECM13
MF-induced ECM deformation was calculated from bead displacements (Fig. 1c) using particle image velocimetry (PIV) for 0–8 h following MF attachment (Fig. 1d)

Summary

Introduction

We demonstrate that local remodeling of collagen fibers by contracting MFs provides far-ranging mechanical cues in the ECM that attract and guide Mφ over long distances. We propose that mechanical signals support Mφ attraction to MFs during normal and dysregulated tissue repair where the secreted growth factor environment may be too complex to provide clear chemotactic clues

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Conclusion