Nanotopography Directs Mesenchymal Stem Cells to Osteoblast Lineage Through Regulation of microRNA-SMAD-BMP-2 Circuit

Abstract

The aim of this study was to investigate if chemically produced nanotopography on titanium (Ti) surface induces osteoblast differentiation of cultured human bone marrow mesenchymal stem cells (hMSCs) by regulating the expression of microRNAs (miRs). It was demonstrated that Ti with nanotopography induces osteoblast differentiation of hMSCs as evidenced by upregulation of osteoblast specific markers compared with untreated (control) Ti at day 4. At this time-point, miR-sequencing analysis revealed that 20 miRs were upregulated (>2 fold) while 20 miRs were downregulated (>3 fold) in hMSCs grown on Ti with nanotopography compared with control Ti. Three miRs, namely miR-4448, -4708 and -4773, which were significantly downregulated (>5 fold) by Ti with nanotopography affect osteoblast differentiation of hMSCs. These miRs that directly target SMAD1 and SMAD4, both key transducers of the bone morphogenetic protein 2 (BMP-2) osteogenic signal, were upregulated by Ti with nanotopography. Overexpression of miR-4448, -4708 and 4773 in MC3T3-E1 pre-osteoblasts noticeably inhibited gene and protein expression of SMAD1 and SMAD4 and therefore repressed the gene expression of key bone markers. Additionally, it was observed that the treatment with BMP-2 displayed a higher osteogenic effect on MC3T3-E1 cells grown on Ti with nanotopography compared with control Ti, suggesting that the BMP-2 signaling pathway was more effective on this surface. Taken together, these results indicate that a complex regulatory network involving a miR-SMAD-BMP-2 circuit governs the osteoblast differentiation induced by Ti with nanotopography.

The effect of collagen coating on titanium with nanotopography on in vitro osteogenesis

“…The SEM and AFM analyses confirmed that a nanotopography characterized by nanopits is generated by etching the Ti surface with H 2 SO 4 /H 2 O 2 solution, similar to our previous findings . Also, in agreement with observations that collagen coating does not alter the Ti topography, no differences in the nanotopographic features of the Ti surface were detected after the collagen layer deposition .…”

Grid-like surface structures in thermoplastic polyurethane induce anti-inflammatory and anti-fibrotic processes in bone marrow-derived mesenchymal stem cells

“…The absence of both osteo-and adipogenic differentiation is a first major finding since uncontrolled and unsuitable differentiation processes must be avoided in a putative therapeutic setting especially in ectopic settings like the neural system. It has been demonstrated previously that micro-or nanostructuring of the substrate can induce neuronal or osteogenic differentiation processes of MSCs [34][35][36][37][38][39]. As one example, investigations with square-shaped or round-shaped microwells in polystyrene (side length or diameter of 10, 25, and 50 µm, respectively) showed that only the substrate with 50 µm square-shaped microwells promoted osteogenic differentiation of adipose tissue-derived MSCs [40].…”

Designer Supersurfaces via Bioinspiration and Biomimetics for Dental Materials and Structures

“…Much work has been carried out to unravel the mechanisms involved in surface contact and gene expression. The principal contact point is the subcellular macromolecular focal adhesion, which is joined between the cell cytoskeleton and extracellular matrices [7]. The association and clustering of these objects with the matrix is an important effect that allows sensing of mechanical forces.…”

“…Programmable biomaterials with influential topography are a realistic prospect for interplay with human cells and bacteria cells. There is tremendous array of data showing the diverse pairings of nanotopography arrays with fibroblasts, endothelial, epithelial, pluripotent, mesenchymal and embryonic [3][4][5][6][7][8][9][10][11][12]. There are numerous instances of conflicting results but there are strong trends emerging.…”