Human mesenchymal stem cells (hMSCs) have been extensively explored for drug delivery applications due to their safety, immunomodulatory properties, and ability to differentiate into new tissues. The experiments presented in this study were designed to determine peptide-based mechanisms to increase the adenoviral transduction of hMSCs for the purpose of improving their capacity as drug delivery vehicles. Specifically, we demonstrated that cyclic- RGD peptides increased the internalization of adenoviruses into MSCs. MSCs treated with cyclic-RGD peptides had a transduction efficiency of 76.6%±4%, which was significantly greater than the 23.5%±12.2% transduction efficiency of untreated stem cells (P<0.05). Blocking endocytosis with inhibitors of dynamin or actin polymerization decreased the cyclic-RGD-mediated increase in transduction efficiency. MSCs treated with cyclic-RGD and adenoviruses carrying the gene for bone morphogenetic protein-2 produced significantly greater concentrations of this growth factor compared to stem cells treated with only adenoviruses or adenoviruses cocultured with cyclic-RAD peptides. Furthermore, this stem cell-produced bone morphogenetic protein induced alkaline phosphatase expression in C2C12 cells indicating growth factor bioactivity. Taken together, these studies suggest that cyclic-RGD peptides could be used to increase the adenoviral transduction of hMSCs and increase their therapeutic potential.
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