Cell material property dictates stress-induced spreading and differentiation in embryonic stem cells

Growing evidence suggests that physical microenvironments and mechanical stresses, besides soluble factors, help direct mesenchymal stem cell fate. However, biological responses to a local force in embryonic stem (ES) cells remain elusive. Here we show that a local cyclic stress via focal adhesions induced spreading in mouse ES (mES) cells but not in mES cell-differentiated (ESD) cells that were 10-fold stiffer. This response was dictated by the cell material property (cell softness), suggesting that a threshold cell deformation is the key setpoint for triggering spreading responses. Traction quantification and pharmacological or shRNA intervention revealed that myosin II contractility, F-actin, Src, or Cdc42 were essential in the spreading response. The applied stress led to Oct3/4 gene downregulation in mES cells. Our findings demonstrate that cell softness dictates cellular sensitivity to force, suggesting that local small forces might play far more important roles in early developments of soft embryos than previously appreciated.