The nanoscale geometry of TiO2 nanotubes influences the osteogenic differentiation of human adipose-derived stem cells by modulating H3K4 trimethylation

Nanostructured materials can direct stem cell lineage commitment solely by their various, but controllable, geometric cues, which would be very important for their future application in bone tissue engineering and bone regeneration. However, the mechanisms by which nano-geometric cues dictate the osteogenic differentiation of stem cells remain unclear. Epigenetics is central to cellular differentiation, a process that regulates heritable and long-lasting alterations in gene expression without changing the DNA sequence. Here, we explored the varied osteogenic behaviors of human adipose-derived stem cells (hASCs) on titanium dioxide (TiO2) nanotube arrays of different diameters. Both in vitro and in vivo studies demonstrated that the nanoscale geometry influenced cellular differentiation and TiO2 nanotubes with a diameter of 70 nm was the optimal dimension for the osteogenic differentiation of hASCs. Moreover, we observed that TiO2 nanotubes promoted the osteogenic differentiation of hASCs by upregulating methylation level of histone H3 at lysine 4 (H3K4) in the promoter regions of osteogenic genes Runx2 and osteocalcin, by inhibiting demethylase retinoblastoma binding protein 2 (RBP2). These results revealed, for the first time, the epigenetic mechanism by which nanotopography directs stem cell fate.