Physical limits of cell migration: Control by ECM space and nuclear deformation and tuning by proteolysis and traction force

TLDR

Cell migration in 3D tissue is governed by a balance between cell deformability and physical constraints, and is further modulated by ECM degradation via MMPs and integrin‑actomyosin mechanocoupling. The study seeks to determine how these factors cooperate when spatial confinement limits migration. Using MMP‑degradable and nondegradable collagen lattices of varying porosity, the authors quantified migration limits imposed by physical arrest. They found that MMP‑independent migration decreases linearly with pore size and nuclear deformation, arresting when the nucleus occupies 10% of the pore cross‑section, while residual migration under confinement depends on MMP‑mediated ECM cleavage and integrin‑actomyosin forces that jointly propel the nucleus, showing that scaffold porosity and nuclear deformation set migration limits modulated by pericellular collagenolysis and mechanocoupling.

Abstract

Cell migration through 3D tissue depends on a physicochemical balance between cell deformability and physical tissue constraints. Migration rates are further governed by the capacity to degrade ECM by proteolytic enzymes, particularly matrix metalloproteinases (MMPs), and integrin- and actomyosin-mediated mechanocoupling. Yet, how these parameters cooperate when space is confined remains unclear. Using MMP-degradable collagen lattices or nondegradable substrates of varying porosity, we quantitatively identify the limits of cell migration by physical arrest. MMP-independent migration declined as linear function of pore size and with deformation of the nucleus, with arrest reached at 10% of the nuclear cross section (tumor cells, 7 µm2; T cells, 4 µm2; neutrophils, 2 µm2). Residual migration under space restriction strongly depended upon MMP-dependent ECM cleavage by enlarging matrix pore diameters, and integrin- and actomyosin-dependent force generation, which jointly propelled the nucleus. The limits of interstitial cell migration thus depend upon scaffold porosity and deformation of the nucleus, with pericellular collagenolysis and mechanocoupling as modulators.