Oscillatory shear stress mediates directional reorganization of actin cytoskeleton and alters differentiation propensity of mesenchymal stem cells.

ABSTRACT

Shear stress stimuli differentially regulate cellular functions based on the pattern, magnitude as well as duration of the flow. Shear stress can modify intracellular kinase activities and cytoskeleton reorganization to result in changes of cell behavior. Mesenchymal stem cells (MSCs) are mechano-sensitive cells, but little is known about the effects of oscillatory shear stress (OS). In this study, we demonstrate that OS of 0.5 ± 4 dyn/cm(2) induces directional reorganization of F-actin to mediate the fate choice of MSCs through the regulation of ß-catenin. We also found that intercellular junction molecules are the predominant mechanosensors of OS in MSCs to deliver the signals that result in directional rearrangement of F-actin, as well as the increase of phosphorylated ß-catenin (pß-catenin) after 30 minutes of OS stimulation. Depolymerization of F-actin and increase in pß-catenin also lead to the upregulation of Wnt inhibitory factors sclerostin and dickkopf-1. Inhibition of ß-catenin/Wnt signaling pathway is accompanied by the upregulation of sex determining region Y-box2 and NANOG to control self-renewal. In conclusion, the reorganization of actin cytoskeleton and increase in ß-catenin phosphorylation triggered by OS regulate the expression of pluripotency genes via the ß-catenin/Wnt signaling pathway to differentially direct fate choices of MSCs at different time points. Results from this study have provided new information regarding how MSCs respond to mechanical cues from their microenvironment in a time-dependent fashion, and such biophysical stimuli could be administered to guide the fate and differentiation of stem cells in addition to conventional biochemical approaches.