Abstract
BackgroundPeriodontitis is a widespread infectious disease ultimately resulting in tooth loss. The number of mesenchymal stem cells (MSCs) in patients with periodontitis is decreased, and MSC functions are impaired. Rescuing the impaired function of MSCs in periodontitis is the key for treatment, especially in a manner independent of exogenous MSCs. Our previous study found that overexpressed insulin-like growth factor binding protein 5 (IGFBP5) could promote exogenous MSC-mediated periodontal tissue regeneration. Here, we investigate the role of IGFBP5 protein in MSCs and periodontal tissue regeneration independent of exogenous MSCs in an inflammatory niche.MethodsTNFα was used to mimic the inflammatory niche. Lentiviral IGFBP5 shRNA was used to silence IGFBP5 and recombinant human IGFBP5 protein (rhIGFBP5) was used to stimulate the periodontal ligament stem cells (PDLSCs) and bone marrow stem cells (BMSCs). The effects of IGFBP5 on PDLSCs were evaluated using the scratch-simulated wound migration, Transwell chemotaxis, alkaline phosphatase (ALP) activity, Alizarin red staining, Cell Counting Kit-8, Western blot, Real-time PCR, Co-IP and ChIP assays. The swine model of periodontitis was used to investigate the functions of IGFBP5 for periodontal regeneration and its anti-inflammation effect.ResultsWe discovered that 0.5 ng/ml rhIGFBP5 protein enhanced the migration, chemotaxis, osteo/dentinogenic differentiation and cell proliferation of MSCs under the inflammatory condition. Moreover, 0.5 ng/ml rhIGFBP5 application could rescue the impaired functions of IGFBP5-silenced-MSCs in the inflammatory niche. Furthermore, local injection of rhIGFBP5 could promote periodontal tissue regeneration and relieve the local inflammation in a minipig model of periodontitis. Mechanistically, we found that BCOR negatively regulated the expression of IGFBP5 in MSCs. BCOR formed a protein complex with histone demethylase KDM6B and raised histone K27 methylation in the IGFBP5 promoter.ConclusionsThis study revealed that rhIGFBP5 could activate the functions of MSCs in an inflammatory niche, provided insight into the mechanism underlying the activated capacities of MSCs, and identified IGFBP5 as a potential cytokine for improving tissue regeneration and periodontitis treatment independent of exogenous MSCs and its potential application in dental clinic.
Highlights
Periodontitis is a widespread infectious disease resulting in tooth loss
This study revealed that rhIGFBP5 could activate the functions of mesenchymal stem cells (MSCs) in an inflammatory niche, provided insight into the mechanism underlying the activated capacities of MSCs, and identified insulin-like growth factor binding protein 5 (IGFBP5) as a potential cytokine for improving tissue regeneration and periodontitis treatment independent of exogenous MSCs and its potential application in dental clinic
Depletion of IGFBP5 inhibited the functions of PDLSCs in the inflammatory condition IGFBP5 was silenced using Lentiviral IGFBP5 Short hairpin RNAs (shRNA) in periodontal ligament stem cells (PDLSCs), the knockdown efficiency was testified by real-time RT-PCR after selection with puromycin (Fig. 1a), and 10 ng/ml tumor necrosis factor alpha (TNFα) was used to mimic the inflammatory condition
Summary
The number of mesenchymal stem cells (MSCs) in patients with periodontitis is decreased, and MSC functions are impaired. Rescuing the impaired function of MSCs in periodontitis is the key for treatment, especially in a manner independent of exogenous MSCs. Our previous study found that overexpressed insulin-like growth factor binding protein 5 (IGFBP5) could promote exogenous MSC-mediated periodontal tissue regeneration. The transplantation of MSCs, as a promising treatment for periodontal tissue regeneration, has made remarkable strides in recent years, some key problems still exist, such as the unclear regulation mechanism of MSCs, security and ethics, etc. The main problem is that the number of periodontal ligament stem cells (PDLSCs) in patients with periodontitis is decreased, and their functions are impaired, which impedes the regeneration of periodontal tissues [16,17,18]. Enhancing the endogenous functions of MSCs in periodontitis is the key for treatment, especially in a manner independent of exogenous MSCs
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