Abstract
Cells select from a diverse repertoire of migration strategies. Recent developments in tunable biomaterials have helped identify how extracellular matrix properties influence migration, however, many settings lack the fibrous architecture characteristic of native tissues. To investigate migration in fibrous contexts, we independently varied the alignment and stiffness of synthetic 3D fiber matrices and identified two phenotypically distinct migration modes. In contrast to stiff matrices where cells migrated continuously in a traditional mesenchymal fashion, cells in deformable matrices stretched matrix fibers to store elastic energy; subsequent adhesion failure triggered sudden matrix recoil and rapid cell translocation. Across a variety of cell types, traction force measurements revealed a relationship between cell contractility and the matrix stiffness where this migration mode occurred optimally. Given the prevalence of fibrous tissues, an understanding of how matrix structure and mechanics influences migration could improve strategies to recruit repair cells to wound sites or inhibit cancer metastasis.
Highlights
Cells select from a diverse repertoire of migration strategies
Recent advances in intravital imaging have revealed that cells can adopt a diverse set of migration strategies involving migration as single cells or collective strands, transitions between mesenchymal, epithelial, and amoeboid migration modes, deformation of the cell body and nucleus to squeeze through matrix pores, and remodeling of matrix structure to bypass the physical barriers presented by the ECM4–6
To better understand how matrix alignment and stiffness of fibrous extracellular matrix (ECM) influence cell migration, we designed and characterized a synthetic ECM mimetic composed of electrospun dextran methacrylate (DexMA) fibers with orthogonal control over fiber alignment and bulk stiffness[25]
Summary
Cells select from a diverse repertoire of migration strategies. Recent developments in tunable biomaterials have helped identify how extracellular matrix properties influence migration, many settings lack the fibrous architecture characteristic of native tissues. Cells alter their morphology to squeeze through small ECM pores, leading to nuclear rupture and ESCRT III-mediated repair[14] or can transition between mesenchymal and amoeboid migration modes via alterations in matrix adhesivity and confinement[15] These studies reducing the complex physical properties of native tissues to sets of orthogonally tunable parameters have increased our mechanistic understanding of cell migration and identified diverse non-proteolytic migration strategies, which may in part explain the failure of therapeutics solely targeting proteolytic activity toward confining metastatic cells to the primary tumor[16]. We find that a variety of mesenchymal cell types employ this migration mode and baseline cell contractility determined by traction force microscopy (TFM) correlates with the optimal matrix stiffness where this migration mode optimally occurs
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