Biological tissues contain micrometer-scale gaps and pores, including those found within extracellular matrix fiber networks, between tightly packed cells, and between blood vessels or nerve bundles and their associated basement membranes. These spaces restrict cell motion to a single-spatial dimension (1D), a feature that is not captured in traditional in vitro cell migration assays performed on flat, unconfined two-dimensional (2D) substrates. Mechanical confinement can variably influence cell migration behaviors, and it is presently unclear whether the mechanisms used for migration in 2D unconfined environments are relevant in 1D confined environments. Here, we assessed whether a cell migration simulator and associated parameters previously measured for cells on 2D unconfined compliant hydrogels could predict 1D confined cell migration in microfluidic channels. We manufactured microfluidic devices with narrow channels (60- μ m 2 rectangular cross-sectional area) and tracked human glioma cells that spontaneously migrated within channels. Cell velocities (v exp = 0.51 ± 0.02 μ m min −1 ) were comparable to brain tumor expansion rates measured in the clinic. Using motor-clutch model parameters estimated from cells on unconfined 2D planar hydrogel substrates, simulations predicted similar migration velocities (v sim = 0.37 ± 0.04 μ m min −1 ) and also predicted the effects of drugs targeting the motor-clutch system or cytoskeletal assembly. These results are consistent with glioma cells utilizing a motor-clutch system to migrate in confined environments.
Glioma tumor dispersion involves invading cells escaping the tumor bulk and migrating into the healthy brain parenchyma. Here, they encounter linearly aligned track-like tissue structures such as axon bundles and the perivascular space. These environments also contain micrometer-scale pores that impose mechanical confinement on invading cells. To study glioma cell migration in an in vitro system that reproduces some of these features, we used microfluidic devices with 60 µm 2 cross-sectional area channels that confine cells into one-dimensional (1D) tracks. Individual cell tracking revealed strongly persistent migration at a mean rate of 8.5 ± 0.33 nm s -1 . Notably, a 1D computational cell migration simulator predicts migration behaviors of glioma cells without significant adjustment of parameters estimated from previous experiments on two-dimensional (2D) substrates. Pharmacological inhibitors of integrin-mediated adhesions, myosin II activation, or drugs targeting F-actin assembly or microtubule dynamics influence migration consistent with simulations where relevant parameters are changed. These results suggest that cell parameters calibrated to a motor-clutch model on 2D substrates effectively predict 1D confined migration behaviors a priori. Our results outline a method for testing biophysical mechanisms of tumor cell migration in confined spaces and predicting the effects of anti-motility therapy.
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