Immunomodulatory and potential therapeutic role of mesenchymal stem cells in periodontitis.

Periodontitis is a chronic inflammatory disease leading to alveolar bone destruction, and eventually tooth loss. In genetically or environmentally predisposed individuals periodontopathogenic bacteria trigger an inflammatory immune response where activated macrophages secrete inflammatory cytokines and T helper 17 cells produce interleukin-17, receptor activator of nuclear factor kappa B ligand (RANKL) and tumor necrosis factor-α. Inflammation and the production of RANKL, the key cytokine responsible for osteoclast activation, cause excessive activation of osteoclasts. This results in a decoupling between bone formation and resorption, leading to bone loss. As conventional treatment does not target the inflammatory response and osteoclast activation, its effectiveness is limited. Novel treatments are thus required if we are to cure this disease. Mesenchymal stem cells (MSCs), including those of dental origin, are potent immunomodulators and are known to be suitable for tissue regeneration. MSCs can inhibit the immune response by suppressing T cells, inducing regulatory T cells and converting dendritic cells and macrophages into a regulatory phenotype. Additionally, genetic modulation may enhance the therapeutic potential of MSCs. In the present review the authors describe the potential use of MSCs, either unmodified or engineered for therapeutic purposes in periodontitis, with special emphasis on MSCs from dental pulp and periodontal ligament. The paper envisions that multiple targeting of this inflammatory disease by modulating the immune response, promoting bone regeneration and inhibiting bone resorption might yield significantly improved treatment outcomes when combined with conventional treatment modalities.

Antiinflammatory effect of BPC 157 on experimental periodontitis in rats.

The pentadecapeptide BPC 157 has been shown to have anti-inflammatory and wound healing effects on multiple target tissues and organs. The purpose of the present study was to investigate the effect of BPC 157 on inflammation and bone resorption in experimental periodontitis in rats. First the acute effect of BPC was tested on gingival blood flow by laser doppler flowmetry. Then periodontitis was produced by a silk ligature placed around the lower left first molar. Rats were treated with BPC 157 (once daily for 12 days) or vehicle. At day 13, the gingivomucosal tissues encircling the molars were removed on both sides. Inflammation was assessed by Evans blue plasma extravasation technique and by histology. Alveolar bone loss was analyzed by microCT. BPC 157 had no effect on gingivomucosal blood flow. Twelve day ligature caused a significantly increased Evans blue extravasation in the gingivomucosal tissue, histological signs of inflammation, and alveolar bone destruction. BPC 157 treatment significantly reduced both plasma extravasation, histological alterations and alveolar bone resorption. In conclusion, systemic application of BPC 157 does not alter blood circulation in healthy gingiva. Chronic application of the peptide has potent antiinflammatory effects on periodontal tissues in ligature induced periodontitis in rats. Taken together, this proof of concept study suggests that BPC 157 may represent a new peptide candidate in the treatment of periodontal disease.

Differentiation potential of stem cells from human dental origin - promise for tissue engineering.

Recent studies have revealed the existence of stem cells in various human tissues including dental structures. We aimed to establish primary cell cultures from human dental pulp and periodontal ligament, to identify multipotential adult stem cells in these cultures, and to study the differentiation capacity of these cells to osteogenic and to neuronal fates. Dental pulp and the periodontal ligament were isolated from extracted human wisdom teeth. The extracellular matrix was enzymatically degraded to obtain isolated cells for culturing. Both dental pulp and periodontal ligament derived cultures showed high proliferative capacity and contained a cell population expressing the STRO-1 mesenchymal stem cell marker. Osteogenic induction by pharmacological stimulation resulted in mineralized differentiation as shown by Alizarin red staining in both cultures. When already described standard neurodifferentiation protocols were used, cultures exhibited only transient neurodifferentiation followed by either redifferentiation into a fibroblast-like phenotype or massive cell death. Our new three-step neurodifferentiation protocol consisting of (1) epigenetic reprogramming, then (2) simultaneous PKC/PKA activation, followed by (3) incubation in a neurotrophic medium resulted in robust neurodifferentiation in both pulp and periodontal ligament cultures shown by cell morphology, immunocytochemistry and real time PCR for vimentin and neuron-specific enolase. In conclusion, we report the isolation, culture and characterization of stem cell containing cultures from both human dental pulp and periodontal ligament. Furthermore, our data clearly show that both cultures differentiate into mineralized cells or to a neuronal fate in response to appropriate pharmacological stimuli. Therefore, these cells have high potential to serve as resources for tissue engineering not only for dental or bone reconstruction, but also for neuroregenerative treatments.