Mechanics-driven nuclear localization of YAP can be reversed by N-cadherin ligation in mesenchymal stem cells

Abstract

Mesenchymal stem cells adopt differentiation pathways based upon cumulative effects of mechanosensing. A cell’s mechanical microenvironment changes substantially over the course of development, beginning from the early stages in which cells are typically surrounded by other cells and continuing through later stages in which cells are typically surrounded by extracellular matrix. How cells erase the memory of some of these mechanical microenvironments while locking in memory of others is unknown. Here, we develop a material and culture system for modifying and measuring the degree to which cells retain cumulative effects of mechanosensing. Using this system, we discover that effects of the RGD adhesive motif of fibronectin (representative of extracellular matrix), known to impart what is often termed “mechanical memory” in mesenchymal stem cells via nuclear YAP localization, are erased by the HAVDI adhesive motif of the N-cadherin (representative of cell-cell contacts). These effects can be explained by a motor clutch model that relates cellular traction force, nuclear deformation, and resulting nuclear YAP re-localization. Results demonstrate that controlled storage and removal of proteins associated with mechanical memory in mesenchymal stem cells is possible through defined and programmable material systems.

Reversing the Epithelial–Mesenchymal Transition in Metastatic Cancer Cells Using CD146-Targeted Black Phosphorus Nanosheets and a Mild Photothermal Treatment

“…The loss of lamellipodia and dorsal/ventral stress fibers ( i.e. , two traits distinctive of mesenchymal-type cells) , and the appearance of a circumferential actin network ( i.e. , a typical epithelial feature) , imply the phenotypic switch of the cancer cells from a mesenchymal to an epithelial state.…”

How the mechanical microenvironment of stem cell growth affects their differentiation: a review

“…Experiments in which stem cells respond to a mechanical environment sometimes show results that are contrary to previous studies [ 168 ], possibly because the cells have a memory of past mechanical cues and this memory remains useful for the behaviour of the stem cells over time [ 169 ]. By storing and removing proteins associated with mechanical memory [ 170 ], it is possible to alter cell fate, which also provides a direction for stem cell research. The role of stem cell differentiation in medicine is no longer in doubt.…”

Substrate stiffness engineered to replicate disease conditions influence senescence and fibrotic responses in primary lung fibroblasts

“…This made the assessment of YAP translocation challenging as the density of fibroblasts on day 7 were higher than optimal for this readout. In addition, YAP translocation is a swift process as cytoplasmic/nuclear levels can be stable within 1 day after changing the stiffness (81). This could have implications for measuring YAP translocation as the regulatory effect may have been partially diminished demonstrating a weaker effect.…”