RESUMEN
Cell migration, which is central to many biological processes including wound healing and cancer progression, is sensitive to environmental stiffness, and many cell types exhibit a stiffness optimum, at which migration is maximal. Here we present a cell migration simulator that predicts a stiffness optimum that can be shifted by altering the number of active molecular motors and clutches. This prediction is verified experimentally by comparing cell traction and F-actin retrograde flow for two cell types with differing amounts of active motors and clutches: embryonic chick forebrain neurons (ECFNs; optimum â¼1 kPa) and U251 glioma cells (optimum â¼100 kPa). In addition, the model predicts, and experiments confirm, that the stiffness optimum of U251 glioma cell migration, morphology and F-actin retrograde flow rate can be shifted to lower stiffness by simultaneous drug inhibition of myosin II motors and integrin-mediated adhesions.
Asunto(s)
Actinas/metabolismo , Movimiento Celular , Glioma/patología , Neuronas/citología , Prosencéfalo/patología , Citoesqueleto de Actina/metabolismo , Algoritmos , Animales , Adhesión Celular , Línea Celular Tumoral , Embrión de Pollo , Colágeno/química , Progresión de la Enfermedad , Módulo de Elasticidad , Humanos , Integrinas/metabolismo , Ratones , Modelos Biológicos , Modelos Estadísticos , Miosina Tipo II/metabolismo , ARN Mensajero/metabolismoRESUMEN
Cells sense the environment's mechanical stiffness to control their own shape, migration, and fate. To better understand stiffness sensing, we constructed a stochastic model of the "motor-clutch" force transmission system, where molecular clutches link F-actin to the substrate and mechanically resist myosin-driven F-actin retrograde flow. The model predicts two distinct regimes: (i) "frictional slippage," with fast retrograde flow and low traction forces on stiff substrates and (ii) oscillatory "load-and-fail" dynamics, with slower retrograde flow and higher traction forces on soft substrates. We experimentally confirmed these model predictions in embryonic chick forebrain neurons by measuring the nanoscale dynamics of single-growth-cone filopodia. Furthermore, we experimentally observed a model-predicted switch in F-actin dynamics around an elastic modulus of 1 kilopascal. Thus, a motor-clutch system inherently senses and responds to the mechanical stiffness of the local environment.