Dasatinib Promotes Chondrogenic Differentiation of Human Mesenchymal Stem Cells via the Src/Hippo-YAP Signaling Pathway

Mesenchymal stem cells (MSCs) are progenitors of chondrocytes and could be used as a potential therapy for cartilage defects in diarthrodial joints. However, promoting chondrogenic differentiation of MSCs remains a daunting challenge. As a small molecular drug, dasatinib can promote MSC differentiation, although the exact mechanisms of chondrogenic differentiation are unclear. In this study, the differentiation of MSCs into osteoblasts, adipocytes, and chondrocytes was assessed by the protein and mRNA levels of osteoblast- and chondrocyte-related proteins using western blotting and real-time polymerase chain reaction, respectively. MSCs were induced to differentiate into chondrocytes or osteoblasts with or without dasatinib in vitro. The effects of dasatinib on cartilage regeneration were also assessed in vivo in a rabbit model of full-thickness cartilage defects using methacrylate gelatin hydrogel as scaffolds. Dasatinib promoted chondrogenic differentiation and inhibited osteogenic differentiation of MSCs. Furthermore, dasatinib significantly inhibited the expression of YAP and TAZ and the phosphorylation of Src, but it enhanced serine phosphorylation of YAP during the chondrogenic differentiation of MSCs in vitro. Inhibition of the Hippo pathway using XMU-MP-1 dramatically suppressed the serine phosphorylation of YAP and chondrogenic differentiation of MSCs. Moreover, we confirmed that the sustained release of dasatinib from the hydrogel promoted rabbit cartilage repair. The results demonstrated that dasatinib might promote chondrogenic differentiation of MSCs via the Src/Hippo-YAP signaling pathway and that hydrogel sustained-release dasatinib had a certain effect on the repair of cartilage defects.