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Local Injection of Allogeneic Stem Cells from Apical Papilla Enhanced Periodontal Tissue Regeneration in Minipig Model of Periodontitis.

ABSTRACT: Background:Discovering suitable seeding cells and simple application technique will be beneficial for MSC-mediated treatment of periodontitis. Stem cells from apical papilla (SCAPs) might be the candidate seeding cell for the periodontal tissues regeneration based on their origin and characters. In this research, we investigated the effect of SCAPs on periodontal tissue regeneration in swine by local injection. Methods:We established experimental periodontitis model in miniature pigs and then treated them with SCAPs by local injection. Clinical assessments, computed tomography (CT) scanning, histologic examination, and quantitative measurements were used to evaluate the effect of periodontal tissues regeneration. Results:At 12 weeks after injection, clinical assessments showed that probing depth, gingival recession, and attachment loss values were 5.44±0.77 mm versus 7.33±1.0 mm (p<0.01), 2.33±0.33 mm versus 2.11±0.69 mm (p>0.05), and 7.78±0.84 mm versus 9.44±1.07 mm (p<0.01) in SCAPs group and 0.9% NaCl group, respectively. CT scan results showed a significant increase of 12.86 mm3 alveolar bone regeneration in SCAPs group compared with 0.9% NaCl group. In addition, histopathology results demonstrated remarkable regeneration in SCAPs group, whereas regeneration of periodontal tissue was hardly found in 0.9% NaCl group. Conclusion:Local injection of SCAPs could effectively restore tissue defects brought about by periodontitis in the swine model. Thus, SCAPs, as an easily accessible dental-deriving stem cell, may serve as an alternative application for periodontitis treatment.

SUBMITTER: Li G

PROVIDER: S-EPMC6077668 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Local Injection of Allogeneic Stem Cells from Apical Papilla Enhanced Periodontal Tissue Regeneration in Minipig Model of Periodontitis.

Li Guoqing G Han Nannan N Zhang Xiuli X Yang Haoqing H Cao Yangyang Y Wang Songlin S Fan Zhipeng Z

BioMed research international 20180712

<h4>Background</h4>Discovering suitable seeding cells and simple application technique will be beneficial for MSC-mediated treatment of periodontitis. Stem cells from apical papilla (SCAPs) might be the candidate seeding cell for the periodontal tissues regeneration based on their origin and characters. In this research, we investigated the effect of SCAPs on periodontal tissue regeneration in swine by local injection.<h4>Methods</h4>We established experimental periodontitis model in miniature p ...[more]

PMID: 30112386

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Project description:IntroductionPeriapical alveolar bone loss is the common consequence of apical periodontitis (AP) caused by persistent local inflammation around the apical area. Human stem cells from apical papilla (hSCAPs) play a crucial role in the restoration of bone lesions during AP. Studies have recently identified the critical role of microRNAs (miRNAs) involved in AP pathogenesis, but little is known about their function and potential molecular mechanism, especially in the osteogenesis of hSCAPs during AP. Here, we investigated the role of clinical sample-based specific miRNAs in the osteogenesis of hSCAPs.MethodsDifferential expression of miRNAs were detected in the periapical tissues of normal and patients with AP via transcriptomic analysis, and the expression of miR-199a-5p was confirmed by qRT-PCR. Treatment of hSCAPs with miR-199a-5p mimics while loaded onto beta-tricalcium phosphate (β-TCP) ceramic particle scaffold to explore its effect on osteogenesis in vivo. RNA binding protein immunoprecipitation (RIP) and Luciferase reporter assay were conducted to identify the target gene of miR-199a-5p.ResultsThe expression of miR-199a-5p was decreased in the periapical tissues of AP patients, and miR-199a-5p mimics markedly enhanced cell proliferation and osteogenic differentiation of hSCAPs, while miR-199a-5p antagomir dramatically attenuated hSCAPs osteogenesis. Moreover, we identified and confirmed Interferon Induced Protein with Tetratricopeptide Repeats 2 (IFIT2) as a specific target of miR-199a-5p, and silencing endogenous IFIT2 expression alleviated the inhibitory effect of miR-199a-5p antagomir on the osteogenic differentiation of hSCAPs. Furthermore, miR-199a-5p mimics transfected hSCAPs loaded onto beta-tricalcium phosphate (β-TCP) scaffolds induced robust subcutaneous ectopic bone formation in vivo.DiscussionThese results strengthen our understanding of predictors and facilitators of the key AP miRNAs (miR-199a-5p) in bone lesion repair under periapical inflammatory conditions. And the regulatory networks will be instrumental in exploring the underlying mechanisms of AP and lay the foundation for future regenerative medicine based on dental mesenchymal stem cells.

Project description:BackgroundReconstruction of complex critical-size defects (CSD) in the craniofacial region is a major challenge, and soft tissue regeneration is crucial in determining the therapeutic outcomes of craniofacial CSD. Stem cells from apical papilla (SCAP) are neural crest-derived mesenchymal stem cells (MSCs) that are homologous to cells in craniofacial tissue and represent a promising source for craniofacial tissue regeneration. Exosomes, which contain compound bioactive compounds, are the key factors in stem cell paracrine action. However, the roles of exosomes derived from SCAP (SCAP-Exo) in tissue regeneration are not fully understood. Here, we explored the effects and underlying mechanisms of SCAP-Exo on CSD in maxillofacial soft tissue.MethodsSCAP-Exo were isolated and identified by transmission electron microscopy and nanoparticle tracking analysis. The effects of SCAP-Exo on wound healing and vascularization were detected by measuring the wound area and performing histological and immunofluorescence analysis on the palatal gingival CSD of mice. Real-time live-cell imaging and functional assays were used to assess the effects of SCAP-Exo on the biological functions of endothelial cells (ECs). Furthermore, the molecular mechanisms of SCAP-Exo-mediated EC angiogenesis in vitro were tested by immunofluorescence staining, Western blot, and pull-down assays. Finally, in vivo experiments were carried out to verify whether SCAP-Exo could affect vascularization and wound healing through cell division cycle 42 (Cdc42).ResultsWe found that SCAP-Exo promoted tissue regeneration of palatal gingival CSD by enhancing vascularization in the early phase in vivo and that SCAP-Exo improved the angiogenic capacity of ECs in vitro. Mechanistically, SCAP-Exo elevated cell migration by improving cytoskeletal reorganization of ECs via Cdc42 signalling. Furthermore, we revealed that SCAP-Exo transferred Cdc42 into the cytoplasm of ECs and that the Cdc42 protein could be reused directly by recipient ECs, which resulted in the activation of Cdc42-dependent filopodium formation and elevation in cell migration of ECs.ConclusionThis study demonstrated that SCAP-Exo had a superior effect on angiogenesis and effectively promoted craniofacial soft tissue regeneration. These data provide a new option for SCAP-Exo to be used in a cell-free approach to optimize tissue regeneration in the clinic.

Project description:The aim of this study was to investigate the effects of PLLA nanofibrous microspheres (NF-MS) as a cell delivery carrier in combination with controlled release of BMP-2 from PLGA microspheres on the induction of odontogenic differentiation of human stem cells of apical papilla (SCAP). Injectable NF-MS, which mimic the physical architecture of collagen fibers on the nano scale, were fabricated by combining thermally-induced phase separation techniques with an emulsification process. SCAP cultured in a monolayer or cultured on NF-MS in spinner flasks were treated with 100ng/ml BMP-2 in vitro. Odontogenic differentiation was characterized by measuring alkaline phosphatase activity, odontogenic gene expression levels, calcium content, and dentin sialophosphoprotein accumulation. The results demonstrated that BMP-2 enhanced human SCAP odontogenic differentiation both in monolayer culture and on 3D NF-MS in spinner flask culture in vitro. We also developed and tested a system combining NF-MS with controlled BMP-2 release for dentin regeneration in vivo. The results indicate that controlled release of BMP-2 promoted more mineralization and osteodentin formation compared to a BSA-releasing control in a dose-dependent and time-dependent manner. In summary, the NF-MS combined with controlled release of BMP-2 provides an excellent microenvironment for SCAP to regenerate dentin tissue.Tooth lesion and loss affect masticatory efficiency, speaking function, facial aesthetics and even psychological health. Current treatments depend on "inert" restorative materials, which do not have the healing capacity and may lead to the failure of the restorations over a long term. The aim of this study was to develop an injectable biomaterial and desired growth factor delivery system to support stem cells for mineralized dental tissue regeneration. The study showed that novel injectable and biodegradable nanofibrous microspheres and controlled release of BMP-2 synergistically induce the odontogenic differentiation of human stem cells from the apical papilla and mineralized tissue regeneration, demonstrating the potential of living dental tissue repair.

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Local Injection of Allogeneic Stem Cells from Apical Papilla Enhanced Periodontal Tissue Regeneration in Minipig Model of Periodontitis.

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Local Injection of Allogeneic Stem Cells from Apical Papilla Enhanced Periodontal Tissue Regeneration in Minipig Model of Periodontitis.

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