Micro/nano topography with altered nanotube diameter differentially trigger endoplasmic reticulum stress to mediate bone mesenchymal stem cell osteogenic differentiation

Micro/nano-topography (MNT) can promote osteogenic differentiation of stem cells, but the mechanism of topographical signaling transduction remains unclear. We have confirmed MNT, as a stressor, triggers endoplasmic reticulum (ER) stress and activates unfolded protein response in rat bone marrow mesenchymal stem cells, and such topography-induced ER stress promotes osteogenic differentiation. In order to reveal the influence of nanotube dimensions on ER stress, MNTs containing vertically oriented TiO2 nanotubes of diameters ranging from 30 nm to 100 nm were fabricated on pure titanium (Ti) foils, and ER stress and osteogenic differentiation of cells were systematically studied. After 12 h of cultivation, the transmission electron microscopy showed that cells on MNTs presented gross distortions of rough ER morphology containing the electron-dense material, and the expansion of the ER lumen became more pronounced as the dimension of nanotubes increased. Additionally, PCR and western blotting showed that the ER stress-related gene, the ER chaperone 78 kDa glucose-regulated protein, also known as binding-immunoglobulin protein (GRP78/BiP), was up-regulated, which was consistent with the osteogenesis-inducing ability of MNTs. Based on our previous studies, the findings in this article further revealed the mechanism for topographical cues modulating osteogenic differentiation of cells, which may provide an innovative approach for the optimal design of implant surface topography.