Interplay of cell adhesion matrix stiffness and cell type for non-viral gene delivery

Non-viral gene delivery has the potential to treat a wide array of diseases but has been hindered by limited expression in vivo, possibly due to complex cellular microenvironments at delivery sites. Previous studies have reported that extracellular matrix properties, including stiffness, influence non-viral gene transfection efficiencies. This study reports that the effect of matrix stiffness on non-viral gene delivery differs among cell types due to varying sensitivities to matrix rigidity. Plasmid DNA encoding bone morphogenetic protein (BMP)-2 was delivered to fibroblasts, bone marrow stromal cells, and myoblasts cultured on fibronectin-conjugated poly(ethylene glycol) diacrylate hydrogels with varied elastic moduli, and the cellular uptake and subsequent expression of plasmid DNA were examined. While exogenous BMP-2 expression increased with increasing matrix stiffness for all three cell types, the effects of matrix stiffness were most pronounced for fibroblasts. Mechanistic studies conducted in parallel indicate that matrix stiffness influenced the projected area and nuclear aspect ratio for fibroblasts but had minimal effects on the morphology of bone marrow stromal cells and myoblasts. Overall, we believe that the results of this study will be useful for developing advanced non-viral gene delivery strategies for improved therapeutic efficacy.