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SummaryDental pulp is a connective tissue and has functions that include initiative, formative, protective, nutritive, and reparative activities. However, it has relatively low compliance, because it is enclosed in hard tissue. Its low compliance against damage, such as dental caries, results in the frequent removal of dental pulp during endodontic therapy. Loss of dental pulp frequently leads to fragility of the tooth, and eventually, a deterioration in the patient’s quality of life. With the development of biomaterials such as bioceramics and advances in pulp biology such as the identification of dental pulp stem cells, novel ideas for the preservation of dental pulp, the regenerative therapy of dental pulp, and new biomaterials for direct pulp capping have now been proposed. Therapies for dental pulp are classified into three categories; direct pulp capping, vital pulp amputation, and treatment for non-vital teeth. In this review, we discuss current and future treatment options in these therapies.

Dental epithelial progenitor cells differentiate into various cell types during development of tooth germs. To study this mechanism, we produced immortalized dental epithelial progenitor cells derived from the cervical-loop epithelium of a rat lower incisor. The expression patterns of cytokeratin 14, nerve growth factor receptor p75, amelogenin, Notch2, and alkaline phosphatase were examined by immunohistochemistry in both lower and higher cell densities. The patterns of each were compared in the dental epithelium of rat lower incisors. The results demonstrated that these cells could produce ameloblast lineage cells, stratum intermedium cells, stellate reticulum, and outer enamel epithelium. Furthermore, fibroblast growth factor 10 stimulated proliferation of dental progenitor cells and subsequently increased the number of cells expressing alkaline phosphatase. These results suggest that fibroblast growth factor 10 plays a role in coupling mitogenesis of the cervical-loop cells and the production of stratum intermedium cells in rat incisors.

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Rat incisors grow continuously throughout life. Producing a variety of dental epithelial cells is performed by stem cells located in the cervical loop of the incisor apex. To study the mechanisms for cell differentiation, we established a dental epithelial cell line (HAT-7) originating from a cervical loop epithelium of a rat incisor. Immunochemical studies showed that HAT-7 produced the cells expressing amelogenin, ameloblastin, or alkaline phosphatase (ALP). To illustrate a role of Notch signaling in the determinant of the cell fate, we examined expression patterns of Notch1 and Jagged1 in HAT-7 density dependently. At lower cell density, Notch1- or Jagged1-expressing cells were not seen. However, when they were fully confluent, cells began to express Notch1 or Jagged1 strongly. Some ALP-positive cells were almost consistent with Notch1-expressing cells but not Jagged1-expressing cells. These results suggested that the determinant of direction of differentiation was associated with Notch signaling pathway.

Bone morphogenic proteins (BMPs) stimulate bone formation in vivo and osteoblast differentiation in vitro via a Smad signaling pathway. Recent findings revealed that the activation of nuclear factor-κB (NF-κB) inhibits BMP-induced osteoblast differentiation. Here, we show that NF-κB inhibits BMP signaling by directly targeting the Smad pathway. A selective inhibitor of the classic NF-κB pathway, BAY11-770682, enhanced BMP2-induced ectopic bone formation in vivo. In mouse embryonic fibroblasts (MEFs) prepared from mice deficient in p65, the main subunit of NF-κB, BMP2, induced osteoblastic differentiation via the Smad complex to a greater extent than that in wild-type MEFs. In p65(-/-) MEFs, the BMP2-activated Smad complex bound much more stably to the target element than that in wild-type MEFs without affecting the phosphorylation levels of Smad1/5/8. Overexpression of p65 inhibited BMP2 activity by decreasing the DNA binding of the Smad complex. The C-terminal region, including the TA2 domain, of p65 was essential for inhibiting the BMP-Smad pathway. The C-terminal TA2 domain of p65 associated with the MH1 domain of Smad4 but not Smad1. Taken together, our results suggest that p65 inhibits BMP signaling by blocking the DNA binding of the Smad complex via an interaction with Smad4. Our study also suggests that targeting the association between p65 and Smad4 may help to promote bone regeneration in the treatment of bone diseases.

It is important to develop a suitable three-dimensional scaffold for the regeneration therapy of dental pulp. In the present study, the effects of hyaluronic acid (HA) sponge on responses of the odontoblastic cell line (KN-3 cells) in vitro, as well as responses of amputated dental pulp of rat molar in vivo, were examined. In vitro, KN-3 cells adhered to the stable structure of HA sponge and that of collagen sponge. In vivo, dental pulp proliferation and vessel invasion were observed in both sponges implanted at dentin defect area above amputated dental pulp, and the cell-rich reorganizing tissue was observed in the dentin defect when HA sponge was implanted as compared with collagen sponge. Expression levels of IL-6 and TNF-alpha in KN-3 cells seeded in HA sponge were nearly the same with those in the cells seeded in collagen sponge, while the numbers (0.67 x 10(3) at 1 week and 0.7 x 10(3) at 3 weeks) of granulated leukocytes that invaded into HA sponge from amputated dental pulp was significantly lower than those (1.22 x 10(3) at 1 week and 1.1 x 10(3) at 3 weeks) of collagen sponge (p < 0.01 at 1 week and p < 0.05 at 3 weeks). These results suggest that HA sponge has an appropriate structure, biocompatibility, and biodegradation for use as a scaffold for dental pulp regeneration.

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