Migration of Human Mesenchymal Stem Cells Under Low Shear Stress Mediated by Mitogen-Activated Protein Kinase Signaling

Abstract

Human mesenchymal stem cells (hMSCs) are attractive candidates for cell-based tissue repair approaches and have been used as vectors for delivering therapeutic genes to sites of injury. It is believed that hMSCs are able to detect and respond to shear stress due to blood and interstitial fluid flow through mechanotransduction pathways after transplantation. However, information regarding hMSC migration under shear stress and its mechanism is still limited. In this study, we examined the effect of shear stress on hMSC migration and the role of mitogen-activated protein kinases (MAPKs) in their migration. Shear stress between 0.2 and 10 Pa, which was produced by the flow medium, was exerted on fluorescently labeled hMSCs. Cell migration was evaluated using the scratch wound assay, and images were captured using a microscope equipped with a digital 3CCD camera. The results showed that hMSCs subjected to a shear stress of 0.2 Pa caused notably faster wound closure than statically cultured hMSCs, while migration in the 0.5- and 1-Pa shear stress group did not differ significantly from that in the control group. Shear stress >2 Pa markedly inhibited hMSC migration. hMSCs subjected to a shear stress of 0.2 Pa displayed an increase in extracellular signal-regulated kinases 1/2 (ERK1/2), c-Jun N-terminal kinases (JNK), and p38 MAPK activation for up to 60 min, while a shear stress of 2 Pa abrogated the activation. JNK and p38 MAPK inhibitors completely abolished the effect of shear stress on hMSC migration, while significant differences were observed between the ERK1/2 inhibitor-treated static control and shear stress groups. Taken together, these results demonstrate that low shear stress effectively induces hMSC migration and that JNK and p38 MAPK play more prominent roles in shear stress-induced migration than ERK1/2.