Migration critically meditates osteoblastic differentiation of bone mesenchymal stem cells through activating canonical Wnt signal pathway

Basic cellular events, such as focal adhesion and cytoskeleton organization, have been reported to be actively involved in fate decision process of stem cells, besides chemical and physical cues. Stem cell migration is critical in regulating various stem cell functions, but its influence on MSC differentiation into specific lineages has been rarely exploited. In this study, we used RGD-modified substrates to regulate cell motility though different RGD concentrations and systematically analyzed the correlation between osteoblastic differentiation and cell migration, as well as the role of Wnt signaling pathway. High motility correlated well with the significantly enhanced potential of the MSCs to differentiate into the osteoblastic lineage, as suggested by the significant up regulations of Runx2, ALP, OCN expressions. The results also suggested that enhanced MSC migration efficiently activated the canonical Wnt-beta-catenin pathway and stimulated transcription activities leading to osteoblastic differentiation, likely through internal forces generated dynamically during migration. Blockage of the Wnt-beta-catenin pathway through artificial down-regulation of LRP5/6 expression significantly suppressed the osteoblastic differentiation for samples with high MSC motilities, further corroborating the critical involvement of Wnt/beta-catenin pathway in the cell migration induced mechanotransduction and MSC differentiation into osteoblastic lineage. Our findings provide important insight for understanding the complicate mechanisms involved in MSC fate selection process and bone regeneration, and would have significant implications in the optimal design of bone tissue engineering materials through regulating cell motility.