Mesenchymal stem cells exploit extracellular matrix as mechanotransducer.

While stem cells can sense and respond to physical properties of their environment, the molecular aspects how physical information is translated into biochemical signals remain unknown. Here we show that human mesenchymal stem cells (hMSCs) harvest and assemble plasma fibronectin into their extracellular matrix (ECM) fibrils within 24 hours. hMSCs pro-actively pull on newly assembled fibronectin ECM fibrils, and the fibers are more stretched on rigid than on soft fibronectin-coated polyacrylamide gels. Culturing hMSCs on single stretched fibronectin fibers upregulates hMSC osteogenesis. Osteogenesis was increased when αvβ3 integrins were blocked on relaxed fibronectin fibers, and decreased when α5β1 integrins were blocked or when epidermal growth factor (EGF) receptor signaling was inhibited on stretched fibronectin fibers. This suggests that hMSCs utilize their own contractile forces to translate environmental cues into differential biochemical signals by stretching fibronectin fibrils. Mechanoregulation of fibronectin fibrils may thus serve as check point to regulate hMSC osteogenesis.