Tooth development is characterized by a series of reciprocal epithelial-mesenchymal interactions between the ectoderm and underlying neural crest-derived mesenchyme. Spatiotemporally regulated paracrine signal molecules of several conserved families referred to as developmental genetic toolkits, such as bone morphogenetic proteins (BMPs), fibroblast growth factors (FGFs), sonic hedgehog (Shh), the tumor necrosis factor (TNF) family, and Wnts, play crucial roles in mediating these tissue interactions. However, the developmental biology of tooth root formation has not been fully studied, especially as to how Hertwig’s epithelial root sheath (HERS) is formed, the functional significance of HERS, and the fate of HERS. Recently, several important papers concerning the developmental biology of HERS and tooth root formation have been published by Japanese and Korean research groups. The current special issue features review articles by these authors who introduce their recent data on the developmental biology of tooth root development clarified using their particular strategies. Furthermore, we discuss the perspective of regenerative science and medicine in the field of dentistry. Exact knowledge of the mechanisms of tooth root formation would provide useful information for future regenerative treatments and the application of tissue-engineered teeth in dentistry. Further studies are required to clarify the expression patterns of signal molecules during tooth root formation, and exact knowledge about odontogenic stem cells and improvement of tissue engineering techniques are needed for future regenerative dentistry.

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The tooth root is a foundation structure embedded in the alveolar bone of the jaws. Root formation starts after the completion of crown morphogenesis and proceeds slowly while coordinating the formation of the periodontal tissue that supports the tooth. Although several signaling pathways and transcription factors have been implicated in the regulation of molar crown development, relatively little is known about the regulatory mechanisms governing the transition from crown to root development. The formation of Hertwig’s epithelial root sheath (HERS), consisting of 2 epithelial layers, is a key event in the initiation of root development. Recently, a new hypothesis about the mechanism of HERS formation was proposed based on the results of experiments using Fibroblast growth factor (Fgf)-10-deficient mice. In this review, we discuss this new hypothesis of HERS development and the signaling change for HERS formation during the transition process from crown to root development.

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Tooth development is regulated by reciprocal interactions between epithelial and mesenchymal cells. Several morphological studies suggest that growth factors secreted from these cells regulate tooth development. These growth factors induce undifferentiated cells in the tooth germ to differentiate into tooth-forming cells. Many growth factors are reportedly expressed in the developing tooth, but the key molecule underlying tooth root development is still unknown. There is a considerable amount of data on the expression and function of bone morphogenetic proteins (BMPs) during tooth development, but the relationship between BMPs and tooth root development has not been analyzed extensively. This prompted us to examine the expression patterns of BMP4 and BMP receptors (BMPRs) at the apical region of the tooth germ during mouse tooth root development. We found that BMP4 was strictly expressed in the apical mesenchyme, and that BMPRs were localized in Hertwig’s epithelial root sheath (HERS). We also investigated the possible roles of BMP4 in HERS during the early stage of tooth root development. Our organ-culture results indicated that BMP4 regulates HERS formation via harmonious interactions with its own antagonist, noggin, by preventing elongation and maintaining cell proliferation. BMP4 may therefore be useful in various tissue-engineering applications as a regulator of tooth root formation.

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Cell-based therapy combined with tissue stem cells and tissue-engineering technology is believed to be a very powerful tool for regeneration of the tooth root and periodontal tissue in the future. The molecular mechanism of tooth root development is useful for this therapy; however, not enough basic information has been accumulated about tooth root development. Reciprocal epithelial-mesenchymal interactions, polarized growth and complicated morphogenic events are involved in tooth development. Recently, a Sonic hedgehog (Shh)-fibroblast growth factor (Fgfs)-dependent regulatory mechanism was found in the developing tooth roots, in a previous report that dental tissues had zone polarizing activity (ZPA) in the chick limb bud. Shh-Fgfs morphogenetic signaling is conserved in the developing molar tooth roots, but a unique combination of Fgfs is used for molar tooth root development compared to the limb bud patterning process.

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The periodontal ligament (PDL) is a tendon/ligament-like fibrous tissue that connects the tooth root surface and the alveolar bone. General interest has been expressed in PDL development as a model for connective tissue formation because of its ability to adapt to mechanical loading. PDL cell has its origin in the dental follicle (DF) cell, and it begins to differentiate during tooth root development. During apical development of the tooth root, PDL progenitors in DF differentiate into PDL cells to form the PDL; however, the molecular mechanisms of PDL development have not yet been clarified, as PDL lineage-specific markers are not available. We recently established a transcriptome database for the human PDL (KK-Periome database), and screened the genes specifically expressed during PDL development. Initial screening of the database allowed us to identify F-spondin and tenascin-N, which are restricted to DF and PDL cells, respectively. Thus, these could serve as PDL lineage-specific markers that would be useful for investigating the molecular mechanisms of PDL development.

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The detailed features of cementum and PDL remain unknown and specific markers for cementoblasts and PDL cells have not been identified. Moreover, the molecular mechanism of periodontal tissue development, homeostasis and regeneration is also obscure. Since cementum or PDL tissue in previous studies was usually obtained by manual curettage, it has been difficult to isolate pure cementum or PDL. In the current study, laser capture microdissection (LCM) of undecalcified frozen sections of murine mandible was employed for precise tissue isolation and to obtain intact RNA from cementoblasts and PDL cells of the murine mandible. Over 500 tentative cementoblasts and PDL cells were individually captured using an infrared laser. A bioanalyzer detected peaks of 18S and 28S rRNA, suggesting that the quality of RNA was sufficient. Subsequently, mRNA expression in cementoblasts was compared with that in PDL cells by GeneChip analysis, showing that approximately 2,000 genes were differently expressed between those tissues. Serial cementoblast-positive and PDL-negative genes were subjected to real-time RT-PCR analysis to support GeneChip results, using mandible and femur RNA samples. Several genes were expressed at higher levels in the mandible than in the femur, suggesting that several genes found in this study might be candidates for cementum-specific markers. In this study, a novel experimental system was established to isolate target tissues from undecalcified frozen sections at the cell unit level and to obtain intact RNA. Our methodologies could help to guide further investigation of mineralized tissues and to explore tissue-specific factors.

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Applying appropriate stress through the teeth is considered essential for maintaining the homeostasis of the jaw. The aim of this study was to clarify the effects of pressure applied via endosseous implants on internal structures of the jaw. A mandible with dental implants for 15 years was analyzed by micro-CT to prepare a finite element model of the mandible, including implants and the surrounding internal microstructures. Based on this model, mechanical analysis was conducted by the three-dimensional finite element method. The results showed that stress distribution was seen in the trabecular bone around the implants. It became clear that pressure is transmitted to mandibular internal structures via implants, and stress is dispersed along internal trabecular alignment.

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We have examined the effect of a unilateral chemical lesion, made in the red nucleus (RN), on feeding and drinking in rats. Kainic acid (0.1 μL, lesion group) or phosphate-buffered saline (0.1 μL, control group) was injected into the left RN. Before injection there was no significant difference between lesion and control groups in the mean number of pellets ingested, the mean number of pellets dropped from the mouth, or the mean number of water drops drunk. The mean number of pellets ingested and the mean number of water drops drunk fell significantly after injection in the lesion group, and then returned to pre-injection levels. Dropping pellets increased greatly in the lesion group after injection. Rats in the lesion group would grasp a pellet and put it into their mouth, but they often did not chew the pellet, or chewed it several times and then dropped it from their mouth. Our study indicates that rats with lesions of the RN cannot chew food and drink well, and that ingestion of food and water decreases temporarily.

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