Enhanced osteogenic differentiation of mesenchymal stem cells on P(VDF‐TrFE) layer coated microelectrodes

Abstract

Electrical stimulation has been proved to be critical to regulate cell behavior. But, cell behavior is also susceptible to multiple parameters of the adverse interferences such as surface current, electrochemical reaction products, and non‐uniform compositions, which often occur during direct electric stimulation. To effectively prevent the adverse interferences, a novel piezoelectric poly(vinylidene fluoride‐trfluoroethylene)(P(VDF‐TrFE)) layer was designed to coat onto the indium tin oxide (ITO) planar microelectrode. We found the electrical stimulation was able to regulate the osteogenic differentiation of mesenchymal stem cells (MSCs) through calcium‐mediated PKC signaling pathway. Meanwhile, the surface charge of the designed P(VDF‐TrFE) coating layer could be easily controlled by the pre‐polarization process, which was demonstrated to trigger integrin‐mediated FAK signaling pathway, finally up‐regulating the osteogenic differentiation of MSCs. Strikingly, the crosstalk in the downstream of the two signaling cascades further strengthened the ERK pathway activation for osteogenic differentiation of MSCs. This P(VDF‐TrFE) layer coated electrical stimulation microelectrodes therefore provide a distinct strategy to manipulate multiple‐elements of biomaterial surface to regulate stem cell fate commitment.

The bioelectrical properties of bone tissue

“…The enhancement of osteogenesis by electroactive scaffolds is thought to be effected by promoting the clustering of focal adhesions (FAs), which in turn trigger the mechanotransduction signaling axis to drive osteogenic differentiation via YAP/TAZ signaling. 91 , 92 Additionally, electroactive scaffolds can also elevate intracellular levels of Ca 2+ ions via modulation of voltage‐gated calcium channels 93 or connexin 43, 94 which in turn promote osteogenic differentiation via the calcineurin/NFAT signaling pathway 52 or the protein kinase C (PKC) signaling pathway. 95 Enhancement of angiogenesis by electroactive scaffolds may involve activation of multiple signaling pathways by electrical stimuli, which include the VEGF/VEGFR, 96 ERK/MAPK, 97 PI3K‐Akt and Rho‐ROCK, 98 Akt, Erk1/2, and JNK 99 signaling pathways.…”

Titanium dioxide nanotubes increase purinergic receptor P2Y6 expression and activate its downstream PKCα-ERK1/2 pathway in bone marrow mesenchymal stem cells under osteogenic induction

“…Similarly, electrical stimulation can activate the ERK pathway to regulate the osteogenic differentiation of BMSCs through the Ca 2+ -mediated PKC signaling pathway [45]. The abnormal in ux of intracellular Ca 2+ can downregulate the expression of PKC-ERK signal, inhibit the osteogenic differentiation of BMSCs, and lead to osteoporosis [46].…”

Electroactive Biomaterials for Facilitating Bone Defect Repair under Pathological Conditions

“…Electroactive scaffolds have been reported to promote the clustering of FAs and the subsequent activation of focal adhesion kinase (FAK), which in turn trigger the mechanotransduction signaling axis to promote osteogenic differentiation via YAP/TAZ transcriptional co-activation of key genes involved in osteogenesis. [108,109] The underlying mechanism is thought to involve a change in the conformation of adsorbed fibronectin via the surface electrical charge, which in turn enhances the binding and clustering of integrin receptors to promote focal adhesion complex formation. [110] Another mechanism of electrical stimulation in osteogenesis involves the triggering of an intracellular influx of Ca 2+ ions via modulation of voltage-gated calcium channels or connexin 43.…”

“…Focal adhesion (FA) associated mechanotransduction signaling pathway Raic et al [ 108] Shen et al [ 109] Ribeiro et al [ 110] Voltage-gated Ca 2+ channels Bagne et al [ 111] Zhuang et al [ 112] Brighton et al [ 113] Connexin 43 mediated influx of Ca 2+ Park et al [ 114] Calcineurin/NFAT signaling Winslow et al [ 115] Wang et al [ 116] Protein Kinase C (PKC) signaling Shen et al [ 109] Liu et al [ 117] Enhancement of angiogenesis/vascularization Secretion of VEGF and other pro-angiogenic cytokines Fonseca et al [ 124] Tzoneva et al [ 126] Bai et al [ 129] ERK/MAPK signaling Sheikh et al [ 125] Akt -ERK1/2 -JNK signaling axis Chen et al [ 127] PI3K -Akt/Rho-ROCK signaling axis Zhao et al [ 128] Inhibition of osteoclastogenesis and bone resorption…”