Mesenchymal stem cell-mediated tissue regeneration is a promising approach for regenerative medicine for a wide range of applications. Here we report a new population of stem cells isolated from the root apical papilla of human teeth (SCAP, stem cells from apical papilla). Using a minipig model, we transplanted both human SCAP and periodontal ligament stem cells (PDLSCs) to generate a root/periodontal complex capable of supporting a porcelain crown, resulting in normal tooth function. This work integrates a stem cell-mediated tissue regeneration strategy, engineered materials for structure, and current dental crown technologies. This hybridized tissue engineering approach led to recovery of tooth strength and appearance.

Mesenchymal stem cells (MSCs) have been isolated from the pulp tissue of permanent teeth (dental pulp stem cells or DPSCs) and deciduous teeth (stem cells from human exfoliated deciduous teeth or SHED). We recently discovered another type of MSCs in the apical papilla of human immature permanent teeth termed stem cells from apical papilla (SCAP). Here we further characterized the apical papilla tissue and stem cell properties of SCAP using histological, immunohistochemical and immunocytofluorescent analyses. We found that apical papilla is distinctive to pulp in terms of containing less cellular and vascular components than those in pulp. Cells in apical papilla proliferated 2-to 3-fold greater than those in pulp in organ cultures. Both SCAP and DPSCs were as potent in osteo/dentinogenic differentiation as MSCs from bone marrows while weaker in adipogenic potential. The immunophenotype of SCAP is similar to that of DPSCs on the osteo/ dentinogenic and growth factor receptor gene profiles. Double staining experiments showed that STRO-1 co-expressed with dentinogenic markers such as bone sialophosphoprotein (BSP), osteocalcin (OCN) and growth factors FGFR1 and TGFβRI in cultured SCAP. Additionally, SCAP express a wide variety of neurogenic markers such as nestin and neurofilament M upon stimulation with a neurogenic medium. We conclude that SCAP are similar to DPSCs but a distinct source of potent dental stem/progenitor cells. Their implications in root development and apexogenesis are discussed.

Stem cell-based regenerative medicine is a promising approach for tissue reconstruction. Here, we showed that pro-inflammatory T cells in the recipients inhibited bone marrow mesenchymal stem cell (BMMSC)-mediated bone formation via T helper 1 (Th1) cytokine interferon (IFN)-γ induced down-regulation of runt-related transcription factor 2 (Runx-2) pathway and tumor necrosis factor (TNF)-α-regulated BMMSC apoptosis. TNF-α converted IFN-γ-activated non-apoptotic Fas to a caspase 3/8-associated apoptotic signaling in BMMSCs through inhibition of nuclear factor kappa B (NFκB), resulting in BMMSC apoptosis. Conversely, reduction of IFN-γ and TNF-α levels by systemic infusion of Foxp3+ regulatory T cells (Tregs) markedly improved BMMSC-based bone regeneration and calvarial defect repair in C57BL6 mice. Furthermore, we showed that local administration of aspirin reduced levels of IFN-γ and TNF-α at the implantation site and significantly improved BMMSC-based calvarial defect repair. These data collectively uncover a previously unrecognized role of recipient T cells in BMMSC-based tissue engineering.

Some clinical case reports have shown that immature permanent teeth with periradicular periodontitis or abscess can undergo apexogenesis after conservative endodontic treatment. A call for a paradigm shift and new protocol for the clinical management of these cases has been brought to attention. Concomitantly, a new population of mesenchymal stem cells residing in the apical papilla of permanent immature teeth recently has been discovered and was termed stem cells from the apical papilla (SCAP). These stem cells appear to be the source of odontoblasts that are responsible for the formation of root dentin. Conservation of these stem cells when treating immature teeth may allow continuous formation of the root to completion. This article reviews current findings on the isolation and characterization of these stem cells. The potential role of these stem cells in the following respects will be discussed: (1) their contribution in continued root maturation in endodontically treated immature teeth with periradicular periodontitis or abscess and (2) their potential utilization for pulp/ dentin regeneration and bioroot engineering. KeywordsApexogenesis; apical papilla; bioroot engineering; dental pulp stem cells; immature teeth; periodontal ligament stem cells; pulp regeneration; stem cells from human exfoliated deciduous teeth; stem cells from the apical papilla A number of recent clinical case reports have revealed the possibilities that many teeth that traditionally would receive apexification may be treated for apexogenesis. A call for a paradigm shift and new protocol for the clinical management of these cases has been made by the authors (1-3). A recent scientific finding, which may explain in part why apexogenesis can occur in these infected immature permanent teeth, is the discovery and isolation of a new population of mesenchymal stem cells (MSCs) residing in the apical papilla of incompletely developed teeth (4,5). These cells are termed stem cells from the apical papilla (SCAP), and they differentiate

Periodontitis is a periodontal tissue infectious disease and the most common cause for tooth loss in adults. It has been linked to many systemic disorders, such as coronary artery disease, stroke, and diabetes. At present, there is no ideal therapeutic approach to cure periodontitis and achieve optimal periodontal tissue regeneration. In this study, we explored the potential of using autologous periodontal ligament stem cells (PDLSCs) to treat periodontal defects in a porcine model of periodontitis. The periodontal lesion was generated in the first molars area of miniature pigs by the surgical removal of bone and subsequent silk ligament suture around the cervical portion of the tooth. Autologous PDLSCs were obtained from extracted teeth of the miniature pigs and then expanded ex vivo to enrich PDLSC numbers. When transplanted into the surgically created periodontal defect areas, PDLSCs were capable of regenerating periodontal tissues, leading to a favorable treatment for periodontitis. This study demonstrates the feasibility of using stem cell-mediated tissue engineering to treat periodontal diseases.