Low-level shear stress induces differentiation of liver cancer stem cells via the Wnt/β-catenin signalling pathway. 
Shear stress-activated cellular signalling is involved in cellular migration, proliferation and differentiation.  However, it remains unclear about the effects of shear stress on the differentiation of liver cancer stem cells (LCSCs).  In this study, using a parallel plated flow chamber system, we found that low-shear stress loading (2 dyne/cm2) for 48 h could significantly inhibit the sphere-forming ability, increase the chemotherapeutic drug sensitivity, downregulate cancer stem cell marker expression and suppress the in vivo tumorigenicity potential of LCSCs.  Moreover, using an atomic force microscope (AFM), we found that shear stress increased the Young's modulus of LCSCs.  These results indicate LCSC's differentiation after shear stress exposure.  In addition, low-shear stress loading suppressed the β-catenin expression in LCSCs.  More importantly, pharmacological activation of Wnt/β-catenin signalling restored the shear stress-suppressed β-catenin expression in LCSCs, and abolished the shear stress-altered sphere-forming ability, chemotherapeutic drug sensitivity, cancer stem cell marker expression, Young's modulus and in vivo tumorigenicity potential of LCSCs.  Our results suggest that low shear stress could induce LCSC differentiation via the Wnt/β-catenin signalling pathways, providing a new insight into the role of shear stress in cancer cell biological behaviors that might contribute to the development of new therapeutic strategies for liver cancer treatment.