On biocompatible implant surfaces, cellular behavior and fate of stem cells are determined not only by microenvironmental signals but also by electrochemical signals. The potential of electric fields (EFs) to stimulate bone growth and bone healing has been widely demonstrated, but the molecular mechanism linking EFs to osteogenic differentiation has remained elusive. Here we show that constant EFs triggered osteogenic induction of mesenchymal stem cells (MSCs) on a defined nanotubular TiO2 substrate. EFs stimulate the formation of plasma membrane protrusions and the transport of connexin 43 to these protrusions. Connexin 43 is required for the EF-induced lasting intracellular calcium increase, which rapidly propagates to neighboring cells by gap junctions. This enables simultaneous osteogenic induction following downstream calcineurin/CAMKII/NFAT signaling. We propose that connexin 43-mediated, EF-induced osteogenic differentiation of MSCs on a defined nanotubular titanium oxide surface may give new insight on therapeutic interventions for bone regeneration and tissue engineering approaches.
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