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The long-term outcome of replanted avulsed permanent teeth is frequently compromised by lack of revascularization, resulting in pulp necrosis. The purpose of this study was to evaluate the effects of vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF-2) on the revascularization of severed human dental pulps. Tooth slices were prepared from non-carious human molars and treated with 0–50 ng/mL rhVEGF165 or rhFGF-2 for 7 days in vitro. Both angiogenic factors enhanced pulp microvessel density compared with untreated controls (p < 0.05). Tooth slices were also treated with 0 or 50 ng/mL rhVEGF165 for one hour prior to implantation into the subcutaneous space of immunodeficient mice. Treatment with rhVEGF165 increased pulp microvessel density in vivo (p < 0.05). These results demonstrate that rhVEGF165 enhanced neovascularization of severed human dental pulps and suggest that topical application of an angiogenic factor prior to replantation might be beneficial for the treatment of avulsed teeth.

Background Human dental pulp stem cells (DPSCs), which have the ability to differentiate into multiple lineages, were recently identified. DPSCs can be collected readily from extracted teeth and are now considered to be a type of mesenchymal stem cell with higher clonogenic and proliferative potential than bone marrow stem cells (BMSCs). Meanwhile, the treatment of severe bone defects, such as fractures, cancers, and congenital abnormalities, remains a great challenge, and novel bone regenerative techniques are highly anticipated. Several studies have previously shown that 4-(4-methoxyphenyl)pyrido[40,30:4,5]thieno[2,3-b]pyridine-2-carboxamide (TH), a helioxanthin derivative, induces osteogenic differentiation of preosteoblastic and mesenchymal cells. However, the osteogenic differentiation activities of TH have only been confirmed in some mouse cell lines. Therefore, in this study, toward the clinical use of TH in humans, we analyzed the effect of TH on the osteogenic differentiation of DPSCs, and the in-vivo osteogenesis ability of TH-induced DPSCs, taking advantage of the simple transplantation system using cell-sheet technology. Methods DPSCs were obtained from dental pulp of the wisdom teeth of five healthy patients (18–22 years old) and cultured in regular medium and osteogenic medium with or without TH. To evaluate osteogenesis of TH-induced DPSCs in vivo, we transplanted DPSC sheets into mouse calvaria defects. Results We demonstrated that osteogenic conditions with TH induce the osteogenic differentiation of DPSCs more efficiently than those without TH and those with bone morphogenetic protein-2. However, regular medium with TH did not induce the osteogenic differentiation of DPSCs. TH induced osteogenesis in both DPSCs and BMSCs, although the gene expression pattern in DPSCs differed from that in BMSCs up to 14 days after induction with TH. Furthermore, we succeeded in bone regeneration in vivo using DPSC sheets with TH treatment, without using any scaffolds or growth factors. Conclusions Our results demonstrate that TH-induced DPSCs are a useful cell source for bone regenerative medicine, and the transplantation of DPSC sheets treated with TH is a convenient scaffold-free method of bone healing.

In tooth extraction sockets, natural healing is usually expected; however, early healing is advantageous for subsequent treatment and leads to improvement in the patient’s quality of life. In recent years, it has been found that dental pulp tissue contains several dental pulp stem cells. The main objective of this study was to verify whether immediate transplantation of dental pulp tissue without any culture process into the extraction socket would promote healing of the socket. To verify this, the rat’s bilateral maxillary second molars were extracted simultaneously, and dental pulp tissue was collected from the extracted teeth. The right extraction socket was immediately transplanted with dental pulp tissue, and the left extraction socket was used as a control. Both sockets were then covered with immediate curing resin. Micro-CT was performed over time, up to 28 days after tooth extraction, bone mineral content was measured, and histological examination was performed. As a result, inflammatory bone resorption had a normal course in both groups after tooth extraction, but bone resorption tended to be suppressed on the 3 days after tooth extraction in the transplant group. In the transplant group, compared to the control group, the radiopaque area increased from the 5 days after tooth extraction onward, and a significant difference was observed on the 7 days after tooth extraction. Furthermore, bone mineral content measurements suggested that bone maturation progressed from earlier in the transplant group, and histological examination confirmed that bone healing was promoted in the transplant group. These findings confirmed that immediate transplantation of dental pulp tissue can promote bone healing in the extraction socket and suggested that this method can be useful as a new method to promote healing in the extraction socket.

Aims/Introduction Dental pulp stem cells (DPSCs) are thought to be an attractive candidate for cell therapy. We recently reported that the transplantation of DPSCs increased nerve conduction velocity and nerve blood flow in diabetic rats. In the present study, we investigated the immunomodulatory effects of DPSC transplantation on diabetic peripheral nerves. Materials and Methods DPSCs were isolated from the dental pulp of Sprague–Dawley rats and expanded in culture. Eight weeks after the streptozotocin injection, DPSCs were transplanted into the unilateral hindlimb skeletal muscles. Four weeks after DPSC transplantation, neurophysiological measurements, inflammatory gene expressions and the number of CD68‐positive cells in sciatic nerves were assessed. To confirm the immunomodulatory effects of DPSCs, the effects of DPSC‐conditioned media on lipopolysaccharide‐stimulated murine macrophage RAW264.7 cells were investigated. Results Diabetic rats showed significant delays in sciatic nerve conduction velocities and decreased sciatic nerve blood flow, all of which were ameliorated by DPSC transplantation. The number of CD68‐positive monocytes/macrophages and the gene expressions of M1 macrophage‐expressed cytokines, tumor necrosis factor‐α and interleukin‐1β, were increased in the sciatic nerves of the diabetic rats. DPSC transplantation significantly decreased monocytes/macrophages and tumor necrosis factor‐α messenger ribonucleic acid expression, and increased the gene expression of the M2 macrophage marker, CD206, in the sciatic nerves of the diabetic rats. The in vitro study showed that DPSC‐conditioned media significantly increased the gene expressions of interleukin‐10 and CD206 in lipopolysaccharide‐stimulated RAW264.7 cells. Conclusions These results suggest that DPSC transplantation promoted macrophages polarization towards anti‐inflammatory M2 phenotypes, which might be one of the therapeutic mechanisms for diabetic polyneuropathy. Effects of DPSC transplantation on the inflammatory mRNA expressions in sciatic nerves. Transplantation of DPSCs significantly decreased TNF‐α gene expression and increased the CD206 gene expression in the sciatic nerves compared with the vehicle‐injected side in diabetic rats.

Objective To report a case of successful allogeneic grafting of mesenchymal dental pulp stem cells (DPSCs) as preliminary findings in a patient with periodontal disease enrolled into clinical trial ISRCTN12831118. Methods Mesenchymal stem cells from the dental pulp of a deciduous tooth from a 7-year-old donor were separated from the pulp chamber and processed via enzymatic digestion and centrifugation. DPSCs were passaged and cultured on a 35 × 13 mm culture dish in minimum essential medium-alpha, without supplementation. After reaching 80% confluency, 5 x 106 allogeneic DPSCs in 250 µl phosphate buffered saline were seeded onto a dry scaffold of lyophilized collagen-polyvinylpyrrolidone sponge placed in the left lower premolar area of a 61-year-old patient with periodontal disease. Surgical access to the lower premolar area was achieved using the flap technique. Results At 3 and 6 months following allogeneic graft, the patient showed no sign of rejection and exhibited decreases in tooth mobility, periodontal pocket depth and bone defect area. Bone mineral density had increased at the graft site. Conclusions Regenerative periodontal therapy using DPSCs of allogeneic origin may be a promising treatment for periodontal disease-induced bone defects.

Neonatal hypoxia-ischemia (HI) is associated to cognitive and motor impairments and until the moment there is no proven treatment. The underlying neuroprotective mechanisms of stem cells are partially understood and include decrease in excitotoxicity, apoptosis and inflammation suppression. This study was conducted in order to test the effects of intracardiac transplantation of human dental pulp stem cells (hDPSCs) for treating HI damage. Seven-day-old Wistar rats were divided into four groups: sham-saline, sham-hDPSCs, HI-saline, and HI-hDPSCs. Motor and cognitive tasks were performed from postnatal day 30. HI-induced cognitive deficits in the novel-object recognition test and in spatial reference memory impairment which were prevented by hDPSCs. No motor impairments were observed in HI animals. Immunofluorescence analysis showed human-positive nuclei in hDPSC-treated animals closely associated with anti-GFAP staining in the lesion scar tissue, suggesting that these cells were able to migrate to the injury site and could be providing support to CNS cells. Our study evidence novel evidence that hDPSC can contribute to the recovery following hypoxia-ischemia and highlight the need of further investigation in order to better understand the exact mechanisms underlying its neuroprotective effects.

Objectives To investigate the potential for pulpal regeneration via autologous transplantation of deciduous tooth pulp into immature necrotic permanent teeth using an experimental dog model. Methods Experimental apical periodontitis was induced in 60 teeth of six Beagle dogs. Following canal disinfection and pulpotomy, autologous deciduous pulp tissue was transplanted into the root canals (n = 30); as controls, contralateral teeth were treated in accordance with the recommendations of the American Association of Endodontists. Radiographic examinations were performed immediately before transplant, as well as 3 and 6 months after transplant. At the 6-month examination, root samples were collected and histological and immunohistochemical analyses were used to examine tissue regeneration. Results Radiographic analysis showed no significant differences in most histopathological parameters examined; however, apical diameter reduction was greater in the experimental group. Histological and immunohistochemical analyses showed that the canal walls of the experimental group had newly formed dentin-like tissue with dentinal tubules, while the control group had cementum-like deposits along the canal wall and apical foramina. Conclusions Autologous transplantation may be useful for regeneration of dental pulp in necrotic young permanent teeth.

This study demonstrated that immortalized dental pulp stem cells (DPSCs) do not form tumors in animals and that immortalized DPSCs can be differentiated into neurons in culture. These results lend support to the use of primary and immortalized DPSCs for future therapeutic approaches to treatment of neurobiological diseases. Dental pulp stem cells (DPSCs) provide an exciting new avenue to study neurogenetic disorders. DPSCs are neural crest‐derived cells with the ability to differentiate into numerous tissues including neurons. The therapeutic potential of stem cell‐derived lines exposed to culturing ex vivo before reintroduction into patients could be limited if the cultured cells acquired tumorigenic potential. We tested whether DPSCs that spontaneously immortalized in culture acquired features of transformed cells. We analyzed immortalized DPSCs for anchorage‐independent growth, genomic instability, and ability to differentiate into neurons. Finally, we tested both spontaneously immortalized and human telomerase reverse transcriptase (hTERT)‐immortalized DPSC lines for the ability to form tumors in immunocompromised animals. Although we observed increased colony‐forming potential in soft agar for the spontaneously immortalized and hTERT‐immortalized DPSC lines relative to low‐passage DPSC, no tumors were detected from any of the DPSC lines tested. We noticed some genomic instability in hTERT‐immortalized DPSCs but not in the spontaneously immortalized lines tested. We determined that immortalized DPSC lines generated in our laboratory, whether spontaneously or induced, have not acquired the potential to form tumors in mice. These data suggest cultured DPSC lines that can be differentiated into neurons may be safe for future in vivo therapy for neurobiological diseases. Significance This study demonstrated that immortalized dental pulp stem cells (DPSCs) do not form tumors in animals and that immortalized DPSCs can be differentiated into neurons in culture. These results lend support to the use of primary and immortalized DPSCs for future therapeutic approaches to treatment of neurobiological diseases.

Strategies aimed at improving spinal cord regeneration after trauma are still challenging neurologists and neuroscientists throughout the world. Many cell-based therapies have been tested, with limited success in terms of functional outcome. In this study, we investigated the effects of human dental pulp cells (HDPCs) in a mouse model of compressive spinal cord injury (SCI). These cells present some advantages, such as the ease of the extraction process, and expression of trophic factors and embryonic markers from both ecto-mesenchymal and mesenchymal components. Young adult female C57/BL6 mice were subjected to laminectomy at T9 and compression of the spinal cord with a vascular clip for 1 min. The cells were transplanted 7 days or 28 days after the lesion, in order to compare the recovery when treatment is applied in a subacute or chronic phase. We performed quantitative analyses of white-matter preservation, trophic-factor expression and quantification, and ultrastructural and functional analysis. Our results for the HDPC-transplanted animals showed better white-matter preservation than the DMEM groups, higher levels of trophic-factor expression in the tissue, better tissue organization, and the presence of many axons being myelinated by either Schwann cells or oligodendrocytes, in addition to the presence of some healthy-appearing intact neurons with synapse contacts on their cell bodies. We also demonstrated that HDPCs were able to express some glial markers such as GFAP and S-100. The functional analysis also showed locomotor improvement in these animals. Based on these findings, we propose that HDPCs may be feasible candidates for therapeutic intervention after SCI and central nervous system disorders in humans.

Until now, the surface markers of multipotent mesenchymal stem cells (MSCs) had not been fully identified. Here, we found that the IGF1 receptor (IGF1R), regarded as a pluripotent marker of embryonic stem cells (ESCs), was also expressed in human dental pulp derived-mesenchymal stem cells (hDSCs), which displayed a potential for both self-renewal and multipotency. hDSC-secreted IGF1 interacted with IGF1R through an autocrine signaling pathway to maintain this self-renewal and proliferation potential. Stereotaxic implantation of immunosorted IGF1R + hDSCs in rats with neonatal hypoxia-ischemia (NHI) promoted neuroplasticity, improving the neurological outcome by increasing expression of the anti-apoptotic protein Bcl-2, which enhanced both neurogenesis and angiogenesis. In addition, treatment with IGF1R + hDSCs significantly modulated neurite regeneration and anti-inflammation in vivo in NHI rats and in vitro in primary cortical cultures under oxygen/glucose deprivation. Autocrine regulatory expression of IGF1R contributed to maintaining the self-renewal capacity of hDSCs. Furthermore, implantation of IGF1R + hDSCs increased neuroplasticity with neurite regeneration and immunomodulation in and the NHI rat model.