Effect of metformin on human periodontal ligament stem cells cultured with polydopamine‐templated hydroxyapatite

Abstract

Polydopamine‐templated hydroxyapatite (tHA) is a type of nano‐biomaterial that can promote osteogenesis in bone tissue engineering. However, high concentrations of tHA stimulate production of reactive oxygen species (ROS), resulting in cell injury and apoptosis. Metformin has been demonstrated to activate the adenosine monophosphate‐activated protein kinase (AMPK) signaling pathway, which induces autophagy and decreases ROS production to prevent apoptosis. The present study was performed to investigate the potential application of tHA in combination with metformin in periodontal bone tissue engineering. Human periodontal ligament stem cells (hPDLSCs) were exposed to tHA in the presence or absence of metformin, and cytocompatibility and osteogenesis were detected by related assays. Additionally, the autophagy signaling pathway was analyzed by western blotting. Polydopamine‐templated hydroxyapatite, in combination with metformin, substantially reduced ROS production and apoptosis, and enhanced proliferation and osteogenic differentiation of hPDLSCs. Enhanced levels of microtubule‐associated protein 1 light chain 3 II and Beclin‐1 were observed after exposure to tHA plus metformin. Expression of phosphorylated AMPK was increased and that of phosphorylated mammalian target of rapamycin (mTOR) was decreased after exposure to tHA plus metformin. Taken together, our results demonstrate that tHA, combined with metformin, increases the viability of hPDLSCs via the AMPK/mTOR signaling pathway by regulating autophagy and further improving the osteogenic effect.

Porous Nanomaterials Targeting Autophagy in Bone Regeneration

“…Further studies have found that HAP-induced autophagy is achieved through the mTOR signaling pathway in a concentration-dependent manner [112] which, in turn, enhances the osteogenic differentiation [112]. Another study verified that polydopamine-templated hydroxyapatite (tHA) resulted in induced cell cytotoxicity and reactive oxygen species (ROS) accumulation by inhibiting the expression of autophagy-related proteins beclin1 and LC3II in human periodontal ligament stem cells (hPDLSCs) [109]. The combination of tHA and metformin may prevent cytotoxicity in hPDLSCs exposed to tHA by reducing ROS via regulations on autophagy-related AMPK/mTOR signaling pathways, an effect that enhances the osteogenic differentiation of hPDLSCs [109].…”

“…Another study verified that polydopamine-templated hydroxyapatite (tHA) resulted in induced cell cytotoxicity and reactive oxygen species (ROS) accumulation by inhibiting the expression of autophagy-related proteins beclin1 and LC3II in human periodontal ligament stem cells (hPDLSCs) [109]. The combination of tHA and metformin may prevent cytotoxicity in hPDLSCs exposed to tHA by reducing ROS via regulations on autophagy-related AMPK/mTOR signaling pathways, an effect that enhances the osteogenic differentiation of hPDLSCs [109]. On the other hand, hierarchically constructed bone-mimetic selenium-doped hydroxyapatite nanoparticles (B-SeHANs) promote the induction of autophagy and apoptosis via the ROS-mediated JNK-activation and AKT/mTOR-inhibition pathways in human MNNG/HOS osteosarcoma cells that suppressed bone tumor growth and reduced bone destruction [110].…”

“…From these points, it could be speculated that autophagy acts like a "double-edged sword" in the treatment of bone regeneration. In this review, we summarize the recent progress of porous nanomaterials, including mesoporous silica-based nanoparticles (including mesoporous silica nanoparticles and mesoporous bioactive glass nanoparticles) [8,25,[106][107][108], mesoporous hydroxyapatite nanoparticles [109][110][111][112], alumina nanoparticles [10,113], and metal titanium dioxide nanotubes [114,115] in promoting bone regeneration via autophagy modulation (Table 1). We especially emphasize the present mechanisms of autophagy regulation induced by PNMs and the role of autophagy regulation in determining cellular fate.…”

Nicotine regulates autophagy of human periodontal ligament cells through α7 nAchR that promotes secretion of inflammatory factors IL-1β and IL-8

“…Dental pulp stem cells activate autophagy as a pro-survival cytoprotective mechanism in response to hydroxyethyl methacrylate injury [ 29 ]. Metformin may prevent cytotoxicity in hPDLCs exposed to Polydopamine-templated hydroxyapatite by reducing ROS via autophagy-related signaling pathways, and may also enhance osteogenic differentiation in hPDLCs [ 30 ].…”

Biological Factors, Metals, and Biomaterials Regulating Osteogenesis through Autophagy

“…Indeed, high concentrations of tHA stimulated ROS production, resulting in cell injury and apoptosis in PDLSCs. Nevertheless, the triggering of the AMPK/mTOR signaling pathway when tHA is in combination with metformin, led to autophagy activation and consequent increased viability of human PDLSCs with a further improvement of the osteogenic effect [149].…”