Cell-matrix force transmission regulates the loss of naïve pluripotency in mouse embryonic stem cells

The first step in the differentiation of mouse embryonic stem cells (mESCs) is the loss of naïve pluripotency. This step involves a major reshaping of cells from a rounded to a spread, adhesive phenotype. Whereas such reshaping is typically associated with increased force transmission to the extracellular matrix (ECM), the magnitude and role of cell-matrix forces in the loss of naïve pluripotency is unknown. Here, we show that cell-matrix forces increase during, and are required for, the loss of naïve pluripotency in mESCs. Using traction force microscopy, we show that mESCs progressively increase cell-traction forces and mechanotransduction markers as naïve pluripotency dissolves. Modulation of force transmission through myosin inhibition, substrate stiffness, or spatial differences within mESC colonies regulates the process. Increased force is triggered by GSK3-mediated signalling, and the effect of force is regulated in part by its transmission to the cell nucleus. Our work unveils a major role of cell-ECM forces in pluripotency dissolution, adding an important aspect to the interplay between biochemical and biophysical cues that drive this process. ### Competing Interest Statement The authors have declared no competing interest.