Kyushu University Academic Staff Educational and Research Activities Database
List of Papers
Hidefumi Maeda Last modified date:2020.04.30

Professor / Oral Rehabilitation / Department of Dental Science / Faculty of Dental Science

1. Hamano S, Tomokiyo A, Hasegawa D, Yuda A, Sugii H, Yoshida S, Mitarai H, Wada N, Maeda H., Functions of beta2-adrenergic receptor in human periodontal ligament cells., J Cell Biochem., 10.1002/jcb.29706., 2020.04.
2. Fujino S, Hamano S, Tomokiyo A, Itoyama T, Hasegawa D, Sugii H, Yoshida S, Washio A, Nozu A, Ono T, Wada N, Kitamura C, Maeda H., Expression and function of dopamine in odontoblasts., J Cell Physiol., 10.1002/jcp.29314., 235, 5, 4376-4387, 2020.05, Dopamine (DA) is produced from tyrosine by tyrosine hydroxylase (TH). A recent study has reported that DA promotes the mineralization of murine preosteoblasts. However, the role of DA in odontoblasts has not been examined. Therefore, in this investigation, we researched the expression of TH and DA in odontoblasts and the effects of DA on the differentiation of preodontoblasts (KN-3 cells). Immunostaining showed that TH and DA were intensely expressed in odontoblasts and preodontoblasts of rat incisors and molars. KN-3 cells expressed D1-like and D2-like receptors for DA. Furthermore, DA promoted odontoblastic differentiation of KN-3 cells, whereas an antagonist of D1-like receptors and a PKA signaling blocker, inhibited such differentiation. However, antagonists of D2-like receptors promoted differentiation. These results suggested that DA in preodontoblasts and odontoblasts might promote odontoblastic differentiation through D1-like receptors, but not D2-like receptors, and PKA signaling in an autocrine or paracrine manner and plays roles in dentinogenesis..
3. 藤野翔香、濱野さゆり、糸山知宏、前田英史., 象牙芽細胞分化におけるドーパミンの発現., 日歯内療誌, 10.1002/jcp.29314., 2020.01.
4. Tomokiyo A, Wada N, Maeda H., Periodontal Ligament Stem Cells: Regenerative Potency in Periodontium. , Stem Cells Dev. 2019 Aug 1;28(15):974-985., 2019.08.
5. Hosoya N, Takigawa T, Horie T, Maeda H, Yamamoto Y, Momoi Y, Yamamoto K, Okiji T., A review of the literature on the efficacy of mineral trioxide aggregate in conservative dentistry., Dent Mater J. Oct 2, 38(5): 693-700, 2019. , 10.4012/dmj.2018-193, 2019.05.
6. Toshimitsu T, Kajiya H, Yasunaga M, Maeshiba M, Fujisaki S, Miyaguchi N, Yamaguchi M, Maeda H, Kojima H, Ohno J., Susceptibility of the wnt/Β-catenin pathway accelerates osteogenic differentiation of human periodontal ligament stem cell spheroids., J Hard Tissue Biol, 28(2): 121-128, 2019, org/10.2485/jhtb.28.121, 2019.02.
7. Yasunaga M, Kajiya H, Toshimitsu T, Nakashima H, Tamaoki S, Ishikawa H, Maeda H, Ohno J., The Early Autophagic Pathway Contributes to Osteogenic Differentiation of Human Periodontal Ligament Stem Cells. , J Hard Tissue Biol, 28(1): 63-70, 2019. , org/10.2485/jhtb.28.63, 28, 1, 2019.01.
8. Arima M, Hasegawa D, Yoshida S, Mitarai H, Tomokiyo A, Hamano S, Sugii H, Wada N, Maeda H., R-spondin 2 promotes osteoblastic differentiation of immature human periodontal ligament cells through the Wnt/-catenin signaling pathway., J Periodont Res., 10.1111/jre.12611, 54, 2, 143-153, 2019.02.
9. Nozu A, Hamano S, Tomokiyo A, Hasegawa D, Sugii H, Yoshida S, Mitarai H, Taniguchi S, Wada N, Maeda H., Senescence and odontoblastic differentiation of dental pulp cells., J Cell Physiol, 10.1002/jcp.26905, 234, 1, 849-859, ??, 2019.01, Cellular senescence has been suggested to be involved in physiological changes of cytokine production. Previous studies showed that the concentration of tumor necrosis factor‐α (TNF‐α) is higher in the blood of aged people compared with that of young people. So far, the precise effects of TNF‐α on the odontoblastic differentiation of pulp cells have been controversial. Therefore, we aimed to clarify how this cytokine affected pulp cells during aging. Human dental pulp cells (HDPCs) were cultured until reaching the plateau of their growth, and the cells were isolated at actively (young HDPCs; yHDPCs) or inactively (senescent HDPCs; sHDPCs) proliferating stages. sHDPCs expressed senescence‐related molecules while yHDPCs did not. When these HDPCs were cultured in an odontoblastinductive medium, both young and senescent cells showed mineralization, but mineralization in sHDPCs was lower compared with yHDPCs. However, the administration of TNF‐α to this culture medium altered these responses: yHDPCs showed downregulated mineralization, while sHDPCs exhibited significantly increased mineralization. Furthermore, the expression of tumor necrosis factor receptor 1 (TNFR1), a receptor of TNF‐α, was significantly upregulated in sHDPCs compared with yHDPCs. Downregulation of TNFR1 expression led to decreased mineralization of TNF‐α‐treated sHDPCs, whereas restored the reduction in TNF‐α‐treated yHDPCs. These results suggested that sHDPCs preserved the odontoblastic differentiation capacity and TNF‐α promoted odontoblastic differentiation of HDPCs with the progress of their population doublings through increased expression of TNFR1. Thus, TNF‐α might exert a different effect on the odontoblastic differentiation of HDPCs depending on their proliferating activity. In addition, the calcification of pulp chamber with age may be related with increased reactivity of pulp cells to TNF‐α..
10. Tomokiyo A, Yoshida S, Hamano S, Hasegawa D, Sugii H, Maeda H., Detection, Characterization, and Clinical Application of Mesenchymal Stem Cells in Periodontal Ligament Tissue, Stem Cells International, ??, 2018.08.
11. Hamano S, Tomokiyo A, Hasegawa D, Yoshida S, Sugii H, Mitarai H, Fujino S, Wada N, Maeda H., Extracellular Matrix from Periodontal Ligament Cells Could Induce the Differentiation of Induced Pluripotent Stem Cells to Periodontal Ligament Stem Cell-Like Cells., Stem Cells Dev., 10.1089/scd.2017.0077, 15;27, 2, 100-111, 2018.01, The periodontal ligament (PDL) plays an important role in anchoring teeth in the bone socket. Damage to the PDL, such as after severe inflammation, can be treated with a therapeutic strategy that uses stem cells derived from PDL tissue (PDLSCs), a strategy that has received intense scrutiny over the past decade. However, there is an insufficient number of PDLSCs within the PDL for treating such damage. Therefore, we sought to induce the differentiation of induced pluripotent stem (iPS) cells into PDLSCs as an initial step toward PDL therapy. To this end, we first induced iPS cells into neural crest (NC)-like cells. We then captured the p75 neurotrophic receptor-positive cells (iPS-NC cells) and cultured them on an extracellular matrix (ECM) produced by human PDL cells (iPS-NC-PDL cells). These iPS-NC-PDL cells showed reduced expression of embryonic stem cell and NC cell markers as compared with iPS and iPS-NC cells, and enrichment of mesenchymal stem cell markers. The cells also had a higher proliferative capacity, multipotency, and elevated expression of PDLrelated markers than iPS-NC cells cultured on fibronectin and laminin (iPS-NC-FL cells) or ECM produced by human skin fibroblast cells (iPS-NC-SF cells). Overall, we present a culture method to produce high number of PDLSC-like cells from iPS cells as a first step toward a strategy for PDL regeneration..
12. Miura A, Tu TTH, Shinohara Y, Mikuzuki L, Kawasaki K, Sugawara S, Suga T, Watanabe T, Watanabe M, Umezaki Y, Yoshikawa T, Motomura H, Takenoshita M, Maeda H, Toyofuku A., Psychiatric comorbidities in patients with Atypical Odontalgia., J Psychosom Res., 10.1016/j.jpsychores.2017.11.001, 104, 35-40, 2018.01.
13. Sugii H, Grimaldi A, Li J, Parada C, Vu-Ho T, Feng J, Jing J, Yuan Y, Guo Y, Maeda H, Chai Y., The Dlx5-FGF10 signaling cascade controls cranial neural crest and myoblast interaction during oropharyngeal patterning and development., Development, 10.1242/dev.155176, 144, 21, 4037-4045, 2017.11.
14. Hasegawa D, Wada N, Yoshida S, Mitarai H, Arima M, Tomokiyo A, Hamano S, Sugii H, Maeda H., Wnt5a Suppresses Osteoblastic Differentiation of Human Periodontal Ligament Stem Cell-like Cells Via Ror2/JNK signaling., J Cell Physiol., 10.1002/jcp.26086., 233, 2, 1752-1762-1762, 2018.02.
15. Hiroyuki Mizumachi, Shinichiro Yoshida, Atsushi Tomokiyo, Daigaku Hasegawa, Sayuri Hamano, Asuka Yuda, 杉井 英樹, Suguru Serita, Hiromi Mitarai, Koori Katsuaki, Naohisa Wada, Hidefumi Maeda, Calcium-sensing receptor-ERK signaling promotes odontoblastic differentiation of human dental pulp cells., 10.1016/j.bone.2017.05.012, 101, 191-201, 2017.05.
16. Hiromi Mitarai, Naohisa Wada, Daigaku Hasegawa, Shinichiro Yoshida, Mai Arima, Atsushi Tomokiyo, Sayuri Hamano, Suguru Serita, Hiroyuki Mizumachi, Hidefumi Maeda, Transgelin mediates TGF-β1-induced proliferation of human periodontal ligament cells., J Peirodont Res, 2017.06.
17. Suguru Serita, Atsushi Tomokiyo, Daigaku Hasegawa, Sayuri Hamano, 杉井 英樹, Shinichiro Yoshida, Hiroyuki Mizumachi, Hiromi Mitarai, Monnouchi Satoshi, Naohisa Wada, Hidefumi Maeda, Transforming growth factor-β-induced gene product-h3 inhibits odontoblastic differentiation of dental pulp cells., Arch Oral Biol., 10.1016/j.archoralbio.2017.02.018, 78, 135-143, 2017.05.
18. Atsushi Tomokiyo, Naohisa Wada, Sayuri Hamano, Daigaku Hasegawa, Hideki Sugii, Shinichiro Yoshida, Hidefumi Maeda, Periodontal Ligament Stem Cells in Regenerative Dentistry for Periodontal Tissues. , 10.15406/jsrt.2015.01.00019, 1, 3, 00019, 2016.07.
19. Shinichiro Yoshida, Naohide Yamamoto, Naohisa Wada, Atsushi Tomokiyo, Daigaku Hasegawa, Sayuri Hamano, Hiromi Mitarai, Monnouchi Satoshi, Asuka Yuda, Hidefumi Maeda, Glial cell line-derived neurotrophic factor from human periodontal ligament cells treated with proinflammatory cytokines promotes neurocytic differentiation of PC12 cells., J Cell Biochem., 10.1002/jcb.25662, 118, 4, 699-708, 2017.04.
20. Shinichiro Yoshida, Naohisa Wada, Daigaku Hasegawa, Miyaji, Hiromi Mitarai, Atsushi Tomokiyo, Sayuri Hamano, Hidefumi Maeda, Semaphorin 3A Induces Odontoblastic Phenotype in Dental Pulp Stem Cells. , J Dent Res., 10.1177/0022034516653085, 95, 11, 1282-1290, 2016.09, In cases of pulp exposure due to deep dental caries or severe traumatic injuries, existing pulp-capping materials have a limited ability
to reconstruct dentin-pulp complexes and can result in pulpectomy because of their low potentials to accelerate dental pulp cell
activities, such as migration, proliferation, and differentiation. Therefore, the development of more effective therapeutic agents has been
anticipated for direct pulp capping. Dental pulp tissues are enriched with dental pulp stem cells (DPSCs). Here, the authors investigated
the effects of semaphorin 3A (Sema3A) on various functions of human DPSCs in vitro and reparative dentin formation in vivo in a rat
dental pulp exposure model. Immunofluorescence staining revealed expression of Sema3A and its receptor Nrp1 (neuropilin 1) in rat
dental pulp tissue and human DPSC clones. Sema3A induced cell migration, chemotaxis, proliferation, and odontoblastic differentiation
of DPSC clones. In addition, Sema3A treatment of DPSC clones increased β-catenin nuclear accumulation, upregulated expression of
the FARP2 gene (FERM, RhoGEF, and pleckstrin domain protein 2), and activated Rac1 in DPSC clones. Furthermore, in the rat dental
pulp exposure model, Sema3A promoted reparative dentin formation with dentin tubules and a well-aligned odontoblast-like cell layer at
the dental pulp exposure site and with novel reparative dentin almost completely covering pulp tissue at 4 wk after direct pulp capping.
These findings suggest that Sema3A could play an important role in dentin regeneration via canonical Wnt/β-catenin signaling. Sema3A
might be an alternative agent for direct pulp capping, which requires further study..
21. Monnouchi Satoshi, Hidefumi Maeda, Asuka Yuda, Suguru Serita, Naohisa Wada, Atsushi Tomokiyo, Akifumi Akamine, Benzo[a]pyrene/aryl hydrocarbon receptor signaling inhibits osteoblastic differentiation and collagen synthesis of human periodontal ligament cells., J Periodont. Res., 10.1111/jre.12355, 51, 6, 779-788, 2016.06, Background and Objective: Cigarette smoking have detrimental effects on periodontal tissue, and is known to be a risk factor for periodontal disease, including the loss of alveolar bone and ligament tissue. However, the direct effects of cigarette smoking on periodontal tissue remain unclear. Recently, we demonstrated that benzo(a)pyrene (BaP), which is a prototypic member of polycyclic aryl hydrocarbons and forms part of the content of cigarettes, attenuated the expression of extracellular matrix remodeling-related genes in human periodontal ligament (PDL) cells (HPDLCs). Thus, we aimed to examine the effects of BaP on the osteoblastic differentiation and collagen synthesis of HPDLCs.
Materials and Methods: HPDLCs were obtained from healthy molars of three patients, and quantitative RT-PCR were performed for gene expression analyses of cytochrome P450 1A1 and 1B1, alkaline phosphatase (ALP), bone sialoprotein, and aryl hydrocarbon receptor (AhR), a receptor for polycyclic aryl hydrocarbons. We have also analyzed the role of the AhR, using 2-methyl-2H-pyrazole-3-carboxylic acid (2-methyl-4-o-tolylazo-phenyl)-amide (CH-223191), which is an AhR antagonist.
Results: The treatment of HPDLCs with BaP reduced mRNA expression of osteogenic genes, ALP activity, mineralization, and collagen synthesis. The treatment with CH-223191 subsequently restored the observed suppressive effects of BaP on HPDLCs.
Conclusions: The present results suggest that BaP exerts inhibitory effects on the maintenance of homeostasis in human PDL tissue, such as osteoblastic differentiation and collagen synthesis of HPDLCs, and that this signaling pathway could be suppressed by preventing the transactivity of AhR. Future studies may unveil a role for the inhibition of AhR as a promising therapeutic agent for periodontal disease caused by cigarette smoking..
22. Urara Tanaka, Terukazu Sanui, Takao Fukuda, Toyoda, K, Taketomi, T, Atomura, R, Yamamichi K, Hidefumi Maeda, Fusanori NISHIMURA, Sprouty2 Inhibition Promotes Proliferation and Migration of Periodontal Ligament Cells., Oral Dis., 10.1111/odi.12369, 21, 8, 977-986, 2015.11, We previously demonstrated that a dominant-negative Sprouty2 (Spry2) mutation promotes osteoblast proliferation and differentiation after basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) stimulation, whereas it diminishes proliferation of gingival epithelial cells, thereby inducing favourable conditions for periodontal tissue regeneration. In this study, we investigated how Spry2 inhibition affects the cellular physiology of periodontal ligament (PDL) cells.
A total of 1-17 PDL cells (multipotent clonal human PDL cell line) were stimulated with bFGF and EGF after transfection of Spry2 siRNA. Cell proliferation, migration, ALP staining, real-time PCR, Western blot and immunofluorescence assays were performed.
ERK1/2 activation and proliferation of 1-17 PDL cells were significantly upregulated by the addition of Spry2 siRNA in the presence of bFGF and EGF. In addition, Spry2 siRNA reduced transcription of osteogenesis-related genes and ALP staining relative to control cells. Furthermore, it increased AKT/phosphatidylinositol 3-kinase (PI3K) phosphorylation; consequently, Rac1 but not Cdc42 was activated, thereby promoting lamellipodia formation, cell proliferation and migration after stimulation by bFGF and EGF.
Spry2 combined with bFGF and EGF stimulation reduced PDL cell migration and proliferation with inducing osteoblastic differentiation. These in vitro findings may provide a molecular basis for novel therapeutic approaches for establishing periodontal tissue regeneration..
23. Toyoda, K, Takao Fukuda, Terukazu Sanui, Urara Tanaka, Yamamichi,K, Atomura, R, Hidefumi Maeda, Atsushi Tomokiyo, Taketomi, T, Takeshi Uchiumi, Fusanori NISHIMURA, Grp78 is Critical for Amelogenin-Induced Cell Migration in a Multipotent Clonal Human Periodontal Ligament Cell Line., J Cell Physiol., 10.1002/jcp.25087, 231, 2, 414-427, 2016.02, Periodontal ligament stem cells (PDLSCs) are known to play a pivotal role in regenerating the periodontium. Amelogenin, which belongs to a family of extracellular matrix (ECM) proteins, is a potential bioactive molecule for periodontal regenerative therapy. However, its downstream target molecules and/or signaling patterns are still unknown. Our recent proteomic study identified glucose-regulated protein 78 (Grp78) as a new amelogenin-binding protein. In this study, we demonstrate, for the first time, the cellular responses induced by the biological interaction between amelogenin and Grp78 in the human undifferentiated PDL cell line 1-17, which possesses the most typical characteristics of PDLSCs. Confocal co-localization experiments revealed the internalization of recombinant amelogenin (rM180) via binding to cell surface Grp78, and the endocytosis was inhibited by the silencing of Grp78 in 1-17 cells. Microarray analysis indicated that rM180 and Grp78 regulate the expression profiles of cell migration-associated genes in 1-17 cells. Moreover, Grp78 overexpression enhanced rM180-induced cell migration and adhesion without affecting cell proliferation, while silencing of Grp78 diminished these activities. Finally, binding of rM180 to Grp78 promoted the formation of lamellipodia, and the simultaneous activation of Rac1 was also demonstrated by NSC23766, a widely accepted Rac1 inhibitor. These results suggest that Grp78 is essential for enhancing amelogenin-induced migration in 1-17 cells. The biological interaction of amelogenin with Grp78 offers significant therapeutic potential for understanding the biological components and specific functions involved in the signal transduction of amelogenin-induced periodontal tissue regeneration..
24. Daigaku Hasegawa, Naohisa Wada, Hidefumi Maeda, Shinichiro Yoshida, Hiromi Mitarai, Atsushi Tomokiyo, Monnouchi Satoshi, Sayuri Hamano, Asuka Yuda, Akifumi Akamine, Wnt5a Induces Collagen Production by Human Periodontal Ligament Cells through Transforming Growth Factor β1-mediated Upregulation of Periostin Expression., J Cell Physiol., 10.1002/jcp.24950., 230, 11, 2647-2660, 2015.11, Wnt5a, a member of the noncanonicalWnt proteins, is known to play important roles in the development of various organs and in postnatal cell functions. However, little is known about the effects of Wnt5a on human periodontal ligament (PDL) cells. In this study, we examined the localization and potential function of Wnt5a in PDL tissue. Immunohistochemical analysis revealed that Wnt5a was expressed predominantly in rat PDL tissue. Semi-quantitative reverse-transcription polymerase chain reaction and western blotting analysis demonstrated that human PDL cells (HPDLCs) expressed Wnt5a and its receptors (Ror2, Fzd2, Fzd4, and Fzd5). Removal of occlusal pressure by extraction of opposing teeth decreased Wnt5a expression in rat PDL tissue, and the expression of Wnt5a and its receptors in HPDLCs was upregulated by exposure to mechanical stress. Stimulation with Wnt5a significantly enhanced the proliferation and migration of HPDLCs. Furthermore, Wnt5a suppressed osteoblastic differentiation of HPDLCs cultivated in osteogenic induction medium, while it significantly enhanced the expression of PDL-related genes, such as periostin, type-I collagen, and fibrillin-1 genes, and the production of collagen in HPDLCs cultivated in normal medium. Both knockdown of periostin gene expression by siRNA and inhibition of TGFβ1 function by neutralizing antibody suppressed the Wnt5a-induced PDL-related gene expression and collagen production in HPDLCs. Interestingly, in HPDLCs cultured with Wnt5a, TGFβ1 neutralizing antibody significantly suppressed periostin expression, while periostin siRNA had no effect on TGFβ1 expression. These results suggest that Wnt5a expressed in PDL tissue plays specific roles in inducing collagen production by PDL cells through TGFβ1-mediated upregulation of periostin expression. This article is protected by copyright. All rights reserved..
25. Myna N. Zakaria, Toru Takeshita, Yukie Shibata, Hidefumi Maeda, Naohisa Wada, Akifumi Akamine, Yoshihisa Yamashita, Microbial community in persistent apical periodontitis: a 16S rRNA gene clone library analysis., Int Endod J., 10.1111/iej.12361, 48, 8, 717-728, 2015.08, AIM:

To characterize the microbial composition of persistent periapical lesions of root filled teeth using a molecular genetics approach.

Apical lesion samples were collected from 12 patients (23-80 years old) who visited the Kyushu University Hospital for apicectomy with persistent periapical lesions associated with root filled teeth. DNA was directly extracted from each sample and the microbial composition was comprehensively analysed using clone library analysis of the 16S rRNA gene. Enterococcus faecalis, Candida albicans and specific fimA genotypes of Porphyromonas gingivalis were confirmed using polymerase chain reaction (PCR) analysis with specific primers.

Bacteria were detected in all samples, and the dominant findings were P. gingivalis (19.9%), Fusobacterium nucleatum (11.2%) and Propionibacterium acnes (9%). Bacterial diversity was greater in symptomatic lesions than in asymptomatic ones. In addition, the following bacteria or bacterial combinations were characteristic to symptomatic lesions: Prevotella spp., Treponema spp., Peptostreptococcaceae sp. HOT-113, Olsenella uli, Slackia exigua, Selemonas infelix, P. gingivalis with type IV fimA, and a combination of P. gingivalis, F. nucleatum, and Peptostreptococcaceae sp. HOT-113 and predominance of Streptococcus spp. On the other hand, neither Enterococcus faecalis nor C. albicans were detected in any of the samples.

Whilst a diverse bacterial species were observed in the persistent apical lesions, some characteristic patterns of bacterial community were found in the symptomatic lesions. The diverse variation of community indicates that bacterial combinations as a community may cause persistent inflammation in periapical tissues rather than specific bacterial species..
26. Ayako Washio, A Nakagawa, Tatsuji Nishihara, Hidefumi Maeda, Chiaki Kitamura, Washio A, Nakagawa A, Nishihara T, Maeda H, Kitamura C. Physicochemical Properties of Newly Developed Bioactive Glass Cement and its Effects on Various Cells., J Biomed Mater Res B Appl Biomater., 10.1002/jbm.b.33209., 103, 2, 373-380, 2015.02, Biomaterials used in dental treatments are expected to have favorable properties such as biocompatibility and an ability to induce tissue formation in dental pulp and periapical tissue, as well as sealing to block external stimuli. Bioactive glasses have been applied in bone engineering, but rarely applied in the field of dentistry. In the present study, bioactive glass cement for dental treatment was developed, and then its physicochemical properties and effects on cell responses were analyzed. To clarify the physicochemical attributes of the cement, field emission scanning electron microscopy, X-ray diffraction, and pH measurement were carried out. Cell attachment, morphology, and viability to the cement were also examined to clarify the effects of the cement on odontoblast-like cells (KN-3 cells), osteoblastic cells (MC3T3-E1 cells), human periodontal ligament stem/progenitor cells and neuro-differentiative cells (PC-12 cells). Hydroxyapatite-like precipitation was formed on the surface of the hardened cement and the pH level changed from pH10 to pH9, then stabilized in simulate body fluid. The cement had no cytotxic effects on these cells, and particulary induced process elongation of PC-12 cells. Our results suggest that the newly developed bioactive glass cement have capability of the application in dental procedures as bioactive cement..
27. Hidefumi Maeda, Akifumi Akamine, Quest for the development of tooth root/periodontal ligament complex by tissue engineering., Integr Mol Med., 10.15761/IMM.1000106, 1, 2, 22-25, 2014.10, The life-span of the tooth is intimately-associated with healthiness of periodontal ligament (PDL) which is a connective tissue situated between bone and cementum
that covers tooth root surface. However, once this tissue is severely damaged by deep caries, periodontitis, and trauma, this leads to severe difficulty in its regeneration,
resulting in tooth loss and decreased quality of life. The development of the therapy for generation and regeneration of the periodontal tissue is an urgent issue.
Therefore, researchers have tried to improve efficiently-generative and regenerative medicine using stem cells, signal molecules, and scaffolds, requisite for tissue
regeneration. In recent studies, a dental follicle tissue that is composed of stem cell population potentially differentiating into PDL tissue, cementum, and alveolar
bone is of current interest. More recently a revolutionary and attractive study reporting the development of bio-hybrid implant that reserved newly-formed cementum/
PDL tissue complex on its surface was introduced. In this review, we describe comprehensive reports that tried to develop the cementum/PDL complex by tissue
engineering and future prospects..
28. Asuka Yuda, Hidefumi Maeda, Fujii Shinsuke, Monnouchi Satoshi, Naohide Yamamoto, naohisa wada, Koori Katsuaki, Atsushi Tomokiyo, Sayuri Hamano, Daigaku Hasegawa, Akifumi Akamine, Effect of CTGF/CCN2 on osteo/cementoblastic and fibroblastic differentiation of a human periodontal ligament stem/progenitor cell line., J Cell Physiol, 10.1002/jcp.24693., 230, 1, 150-159, in press, 2015.01.
29. Hideki Sugii, Hidefumi Maeda, Atsushi Tomokiyo, Naohide Yamamoto, naohisa wada, Koori Katsuaki, Daigaku Hasegawa, Sayuri Hamano, Asuka Yuda, Monnouchi Satoshi, Akifumi Akamine, Effects of Activin A on the phenotypic properties of human periodontal ligament cells., Bone, 10.1016/j.bone.2014.05.021, 66, 62-71, 2014.07.
30. Monnouchi Satoshi, Hidefumi Maeda, Asuka Yuda, Sayuri Hamano, naohisa wada, Atsushi Tomokiyo, Koori Katsuaki, Hideki Sugii, Suguru Serita, Akifumi Akamine, Mechanical induction of interleukin-11 regulates osteo/cementoblastic differentiation of human periodontal ligament stem/progenitor cells., J Periodont Res, 10.1111/jre.12200., 50, 2, 231-239, 2015.02.
31. Hidefumi Maeda, Atsushi Tomokiyo, naohisa wada, Koori Katsuaki, GIICHIRO KAWACHI, Akifumi Akamine, Regeneration of the periodontium for preservation of the damaged tooth, Histol Histopathol, 29, 10, 1249-1262, 2014.10.
32. Yoko Teramatsu, Hidefumi Maeda, Hideki Sugii, Atsushi Tomokiyo, Sayuri Hamano, naohisa wada, Asuka Yuda, Naohide Yamamoto, Koori Katsuaki, Akifumi Akamine, Expression and effects of epidermal growth factor on human periodontal ligament cells, Cell Tissue Res., 10.1007/s00441-014-1877-x., 357, 3, 633-643, 2014.03.
33. Koori Katsuaki, Hidefumi Maeda, Fujii Shinsuke, Atsushi Tomokiyo, GIICHIRO KAWACHI, Daigaku Hasegawa, Sayuri Hamano, Hideki Sugii, naohisa wada, Akifumi Akamine, The roles of calcium-sensing receptor and calcium channel in osteogenic differentiation of undifferentiated periodontal ligament cells. , Cell Tissue Res, 10.1007/s00441-014-1918-5, 357, 3, 707-718, 2014.03.
34. naohisa wada, Hidefumi Maeda, Daigaku Hasegawa, Gronthos S, Bartold PM, Menicanin D, Fujii Shinsuke, Shinichiro Yoshida, Atsushi Tomokiyo, Monnouchi Satoshi, Akifumi Akamine, Semaphorin 3A induces mesenchymal stem-like properties in human periodontal ligament cells, Stem Cell Dev., 2014.05.
35. Takashi Tstsumi, Hiroshi Kajiya, Teruhisa Fukawa, Mina Sasaki, Tetsuomi Nemoto, Takashi Tsuzuki, Yutaka Takahashi, Fujii Shinsuke, Hidefumi Maeda, Koji Okabe, The Potential Role of TRPA1 as a Mechanoreceptor in Human Periodontal Ligament Cells. , Eur J Oral Sci, 121, 6, 538-544, 2013.06.
36. 河野 清美, 前田 英史, 藤井 慎介, 友清 淳, 山本直秀, 和田 尚久, 門野内 聡, 寺松陽子, 濱野さゆり, 郡勝明, 赤峰 昭文, Exposure to transforming growth factor-β1 after basic fibroblast growth factor promotes the fibroblastic differentiation of human periodontal ligament stem/progenitor cell lines., Cell Tissue Res., 352, 2, 249-263, 2013.02.
37. Tomokiyo A, Maeda H, Fujii S, Monnouchi S, Wada N, Hori K, Koori K, Yamamoto N, Teramatsu Y, Akamine A., Alternation of extracellular matrix remodeling and apoptosis by activation of the aryl hydrocarbon receptor pathway in human periodontal ligament cells. , J Cell Biochem., 113, 10, 3093-3103, 2012.10.
38. Yamamoto N, Maeda H, Tomokiyo A, Fujii S, Wada N, Monnouchi S, Kono K, Koori K, Teramatsu Y, Akamine A., Expression and effects of glial cell line-derived neurotrophic factor on periodontal ligament cells. , J Clin Periodontol., 39, 6, 556-564, 2012.06, AIM:

To investigate Glial cell line-derived neurotrophic factor (GDNF) expression in normal and wounded rat periodontal ligament (PDL) and the effects of GDNF on human PDL cells (HPDLCs) migration and extracellular matrix expression in HPDLCs.


The expression of GDNF and GDNF receptors was examined by immunocyto/histochemical analyses. Gene expression in HPDLCs treated with GDNF, interleukin-1 beta (IL-1β), or tumour necrosis factor-alpha (TNF-α) was quantified by quantitative RT-PCR (qRT-PCR). In addition, we examined the migratory effect of GDNF on HPDLCs.


GDNF was expressed in normal rat PDL and cultured HPDLCs. HPDLCs also expressed GDNF receptors. In wounded rat PDL, GDNF expression was up-regulated. QRT-PCR analysis revealed that IL-1β and TNF-α significantly increased the expression of GDNF in HPDLCs. Furthermore, GDNF induced migration of HPDLCs, which was blocked by pre-treatment with the peptide including Arg-Gly-Asp (RGD) sequence, or neutralizing antibodies against integrin αVβ3 or GDNF. Also, GDNF up-regulated expression of bone sialoprotein (BSP) and fibronectin in HPDLCs.


GDNF expression is increased in rat wounded PDL tissue and HPDLCs treated with pro-inflammatory cytokines. GDNF enhances the expression of BSP and fibronectin, and migration in an RGD-dependent manner via the integrin αVβ3. These findings suggest that GDNF may contribute to wound healing in PDL tissue..
39. 前田 英史, 藤井 慎介, 友清 淳, 和田 尚久, 赤峰 昭文, Periodontal tissue engineering: defining the triad., Int J Oral Maxillofac Implants., 28, 6, e461-e471, 2013.11, The idea that somatic stem cells are localized in periodontal ligament (PDL) tissues as PDL stem
cells (PDLSCs) responsible for construction and reconstruction of the periodontium has been
widely accepted. Many dental scientists have attempted to clarify the identity of these PDLSCs,
but the number of PDLSCs localized in PDL tissues is too small to be routinely and conveniently
analyzed. Therefore, researchers have been attempting to develop undifferentiated PDL cell
lines by transducing them with genes that are suitable for immortalization. The present authors
were the first to succeed in establishing two clonal human PDL stem/progenitor cell lines that
possessed multipotency derived from PDL tissues and that expressed PDL-related molecules as
well as neural crest– and embryonic stem–related markers. The differentiation stages of these
cell lines appeared to vary based on their potential to differentiate into other lineage cells, their
response to tissue regeneration–related cytokines, and their behavior when transplanted into
immunodeficient rats. This review describes the phenotypes of these cell lines compared with
reported PDLSCs or other MSCs and discusses contemporary circumstances related to PDL
regenerative medicine. Differential analyses between these two clones will reveal the mechanism
of differentiation of PDLSCs as well as their phenotypes. The results will also allow for the
acquisition of a mass population of PDLSCs or other stem cells directed toward PDL-lineage
cells and to develop an unmet treatment needed for construction and reconstruction of PDL
tissues based on tissue engineering techniques..
40. Tomokiyo A, Maeda H, Fujii S, Monnouchi S, Wada N, Kono K, Koori K, Yamamoto N, Teramatsu Y, Akamine A., A multipotent clonal human periodontal ligament cell line with neural crest cell phenotypes promotes neurocytic differentiation, migration, and survival. , J Cell Physiol., 227, 5, 2040-2050, 2012.02, Repair of injured peripheral nerve is thought to play important roles in tissue homeostasis and regeneration. Recent
experiments have demonstrated enhanced functional recovery of damaged neurons by some types of somatic stem
cells. It remains unclear, however, if periodontal ligament (PDL) stem cells possess such functions. We recently
developed a multipotent clonal human PDL cell line, termed cell line 1-17. Here, we investigated the effects of this
cell line on neurocytic differentiation, migration, and survival. This cell line expressed the neural crest cell marker
genes Slug, SOX10, Nestin, p75NTR, and CD49d and mesenchymal stem cell–related markers CD13, CD29, CD44,
CD71, CD90, CD105, and CD166. Rat adrenal pheochromocytoma cells (PC12 cells) underwent neurocytic
differentiation when co-cultured with cell line 1-17 or in conditioned medium from cell line 1-17 (1-17CM).
ELISA analysis revealed that 1-17CM contained approximately 50 pg/mL nerve growth factor (NGF). Cell line
1-17 induced migration of PC12 cells, which was inhibited by a neutralizing antibody against NGF. Furthermore,
1-17CM exerted antiapoptotic effects on differentiated PC12 cells as evidenced by inhibition of neurite retraction,
reduction in annexin V and caspase-3/7 staining, and induction of Bcl-2 and Bcl-xL mRNA expression. Thus, cell
line 1-17 promoted neurocytic differentiation, migration, and survival through secretion of NGF and possibly
synergistic factors. PDL stem cells may play a role in peripheral nerve reinnervation during PDL regeneration..
41. Maeda H, Tomokiyo A, Fujii S, Wada N, Akamine A., Promise of periodontal ligament stem cells in regeneration of periodontium. , Stem Cell Res Ther. 2(4):33, 2011., 2, 4, 1-3, 2011.07, A great number of patients around the world
experience tooth loss that is attributed to irretrievable
damage of the periodontium caused by deep caries,
severe periodontal diseases or irreversible trauma.
The periodontium is a complex tissue composed
mainly of two soft tissues and two hard tissues; the
former includes the periodontal ligament (PDL) tissue
and gingival tissue, and the latter includes alveolar
bone and cementum covering the tooth root. Tissue
engineering techniques are therefore required for
regeneration of these tissues. In particular, PDL is
a dynamic connective tissue that is subjected to
continual adaptation to maintain tissue size and width,
as well as structural integrity, including ligament
fi bers and bone modeling. PDL tissue is central in
the periodontium to retain the tooth in the bone
socket, and is currently recognized to include somatic
mesenchymal stem cells that could reconstruct the
periodontium. However, successful treatment using
these stem cells to regenerate the periodontium
effi ciently has not yet been developed. In the present
article, we discuss the contemporary standpoints
and approaches for these stem cells in the fi eld of
regenerative medicine in dentistry..
42. Biocompatibility of resin-based sealers- Comparison of Superbond sealer with AH Plus -.
43. Maeda H, Tomokiyo A, Koori K, Monnouchi S, Fujii S, Wada N, Kono K, Yamamoto N, Saito T, Akamine A. , An in vitro evaluation of two resin-based sealers on proliferation and differentiation of human periodontal ligament cells., Int Endod J, 44, 5, 425-431, 2011.05.
44. Kwon SM, Kim SA, Fujii S, Maeda H, Ahn SG, Yoon JH. , Transforming Growth Factor β1 Promotes Migration of Human Periodontal Ligament Cells through Heat Shock Protein 27 Phosphorylation., Biol Pharm Bull, 34, 4, 486-489, 2011.04.
45. Monnouchi S, Maeda H, Fujii S, Tomokiyo A, Hori K, Akamine A, The roles of angiotensin II in stretched periodontal ligament cells., J Dent Res, 90, 2, 181-185, 2011.02.
46. Fujii S, Maeda H, Tomokiyo A, Satoshi M, Hori K, Wada N, Akamine A., The effects of TGF-β1 on the proliferation and differentiation of human periodontal ligament cells and a human PDL stem/progenitor cell line., Cell Tissue Res, 342, 2, 233-242, 2010.12.
47. Maeda H, Nakano T, Tomokiyo A, Fujii S, Wada N, Monnouchi S, Hori K, Akamine A., Mineral Trioxide Aggregate Induces Bone Morphogenetic Protein-2 Expression and Calcification in Human Periodontal Ligament Cells., J Endod, 36巻, 4号, 647-652, 2010.04.
48. Yasuda Y, Tatematsu Y, Fujii S, Maeda H, Akamine A, Torabinejad M, Saito T., Effect of MTAD on the differentiation of osteoblast-like cells., J Endod, 36巻, 2号, 260-263, 2010.02.
49. The Effects of MTA on Human Periodontal Ligament Cells..
50. An Epidemiologic Examination on the Prevalence of the Periodontal Diseases and Oral Pigmentation in Yusho Patients in 2008..
51. Yasuda Y, Inuyama H, Maeda H, Akamine A, Nör JE, Saito T., Cytotoxicity of one-step dentin-bonding agents toward dental pulp and odontoblast-like cells., J Oral Rehabil., 35(12):940-6, 2008, 2008.12.
52. Kano Y, Horie N, Doi S, Aramaki F, Maeda H, Hiragami F, Kawamura K, Motoda H, Koike Y, Akiyama J, Eguchi S, Hashimoto K., Artepillin C derived from propolis induces neurite outgrowth in PC12m3 cells via ERK and p38 MAPK pathways, Neurochem Res, 33(9):1795-803 2008, 2008.09.
53. Tomokiyo A, Maeda H, Fujii S, Wada N, Shima K, Akamine A., Development of a multipotent clonal human periodontal ligament cell line., Differentiation, 76(4):337-347, 2008.04.
54. Fujii S, Maeda H, Wada N, Tomokiyo A, Saito M, Akamine A, Investigating a clonal human periodontal ligament progenitor/stem cell line in vitro and in vivo., J Cell Physiol , 215(3):743-749, 2008.03.
55. SEM images of root canal dentin irrigated with EDTA and NaOCl - Comparison with ultrasonic irrigation -.
56. Cytotoxicity of one-step adhesive resins on dental pulp cells and their effects on differentiation to odontoblasts..
57. An Epidemiological Examination on the Prevalence of the Periodontal Diseases and Oral Pigmentation in Yusho Patients in 2006..
58. In vitro evaluation of cytotoxicity of resin-based root canal sealer.
59. Effects of root-end filling materials on the osteoblast-like differentiation of human periodontal ligament cells.
60. Lu G, Maeda H, Reddy SV, Kurihara N, Leach R, Anderson JL, Roodman GD., Cloning and characterization of the annexin II receptor on human marrow stromal cell., J Biol Chem, 281(41): 30542-30550, 2006.01.
61. Fujii S, Maeda H, Wada N, Kano Y, Akamine A., Establishing and characterizing human periodontal ligament fibroblasts immortalized by SV40T-antigen and hTERT gene transfer., Cell Tissue Res., 324(1): 117-125, 2006.01.
62. Maeda H, Wada N, Fujii S, Akamine A., Fibroblastic cells from human periapical granulation tissue preferentially form calcified matrices in decalcified and boiled rat bone., Cell Tissue Res., 10.1007/s00441-004-1052-x, 320, 1, 135-140, 324(1): 117-125, 2005.04.
63. Wada N, Maeda H, Yoshimine Y, Akamine A., Lipopolysaccharide stimulates osteoprotegerin and receptor activator of NF-kappa B ligand in periodontal ligament fibroblasts through the induction IL-1 beta and TNF-alpha., Bone, 10.1016/j.bone.2004.04.023, 35, 3, 629-635, 35 (3) 629-635., 2004.09.
64. Maeda H, Wada N, Nakamuta H, Akamine A., Human periapical granulation tissue contains osteogenic cells., Cell and Tissue Research, 10.1007/s00441-003-0832-z, 315, 2, 203-208, 315 (2): 203-208, 2004.02.
65. An epidemiologic examination on the prevalence of the periodontal diseases and oral pigmentation in Yusho patients in 2002..
66. Koide M, Maeda H, Roccisana JL, Kawanabe N, Reddy SV., Cytokine regulation and the signaling mechanism of osteoclast inhibitory peptide-1 (OIP-1/hSca) to inhibit osteoclast formation., Journal of Bone and Mineral Research, 18 (3): 458-465, 2003.01.
67. Goto T, Maeda H, Tanaka T., A selective inhibitor of matrix metalloproteases inhibits the migration of isolated osteoclasts by increasing the life span of podosomes., Journal of Bone and Mineral Metabolism, 10.1007/s007740200013, 20, 2, 98-105, 20 (2): 98-105, 2002.01.
68. Koide M, Kurihara N, Maeda H, Reddy SV., Identification of the Functional Domain of Osteoclast Inhibitory Peptide-1/hSca., Journal of Bone and Mineral Research, 17 (1): 111-118, 2002.01.
69. Kurihara N, Menaa C, Maeda H, Haile DJ, Reddy SV., Osteoclast-stimulating Factor Interacts with the Spinal Muscular Atrophy Gene Product to Stimulate Osteoclast Formation., Journal of Biological Chemistry, 276 (44): 41035-41039, 2001.01.
70. Wada N, Maeda H, Tanabe K, Tsuda E, Yano K, Nakamuta H, and Akamine A., Periodontal ligament cells secrete the factor that inhibits osteoclastic differentiation and function: the factor is osteoprotegerin / osteoclastogenesis inhibitory factor., Journal of Periodontal Research, 10.1034/j.1600-0765.2001.00604.x, 36, 1, 56-63, 36 (1): 56-63, 2001.01.
71. Menaa C, Reddy SV, Kurihara N, Maeda H, Anderson D, Cundy T, Cornish J, Singer FR, Bruder JM, Roodman GD., Enhanced RANK ligand expression and responsivity of bone marrow cells in Paget's disease of bone., Journal of Clinical Investigation, 105 (12): 1833-1838, 2000.01.
72. Kukita A, Kukita T, Ouchida M, Maeda H, Yatsuki H, and Kohashi O., Osteoclast-derived zinc finger (OCZF) protein with POZ domain, a possible transcriptional repressor, is involved in osteoclastogenesis., Blood, 94, 6, 1987-1997, 94 (6): 1987-1997, 1999.01.
73. Tanabe K, Nakanishi H, Maeda H, Nishioku T, Hashimoto K, Liou SY, Akamine A, and Yamamoto K., A Predominant Apoptotic Death Pathway of Neuronal PC12 Cells Induced by Activated Microglia Is Displaced by A Non-apoptotic Death Pathway Following Blockage of Caspase-3-dependent Cascade., Journal of Biological Chemistry, 10.1074/jbc.274.22.15725, 274, 22, 15725-15731, 274 (22): 15725-15731, 1999.01.
74. Maeda H, Akasaki K, Yoshimine Y, Akamine A, and Yamamoto K., Limited and Selective Localization of the Lysosomal Membrane Glycoproteins LGP85 and LGP96 in Rat Osteoclasts., Histochemistry and Cell Biology, 10.1007/s004180050354, 111, 4, 245-251, 111 (4): 245-251, 1999.01.
75. Maeda H, Hashiguchi I, Nakamuta H, Toriya Y, Wada N, and Akamine A., Histological Study of Periapical Tissue Healing in the Rat Molar after Retrofilling with Various Materials., Journal of Endodontics, 10.1016/S0099-2399(99)80397-5, 25, 1, 38-42, 25 (1): 38-42, 1999.01.
76. Kukita T, Kukita A, Xu L, Maeda H, and Iijima T, Successful Detection of Active Osteoclasts In Situ by Systemic Administration of an Osteoclast-Specific Monoclonal Antibody., Calcified Tissue International, 10.1007/s002239900506, 63, 2, 148-153, 63 (2): 148-153, 1998.01.
77. Tsukuba T, Sakai H, Yamada M, Maeda H, Hori H, Azuma T, Akamine A, and Yamamoto K., Biochemical Properties of the Monomeric Mutant of Human Cathepsin E Expressed in Chinese Hamster Ovary Cells: Comparison with Dimeric Forms of the Natural and Recombinant Cathepsin E., J Biochemistry, 119, 1, 126-134, 119 (1): 126-134, 1996.01.
78. Kukita T, Kukita A, Nagata K, Maeda H, Kurisu K, Watanabe T, and Iijima T, Novel Cell-Surface Ag Expressed on Rat Osteoclasts Regulating the Function of the Calcitonin Receptor., J Immunology, 153, 11, 5265-5273, 153 (11): 5265-5273, 1995.01.
79. Maeda H, Kukita T, Akamine A, Kukita A, and Iijima T, Localization of Osteopontin in Resorption Lacunae Formed by Osteoclast-like Cells: A Study by a Novel Monoclonal Antibody which Recognizes Rat Osteopontin., Histochemistry, 10.1007/BF00269160, 102, 4, 247-254, 102 (4): 247-254, 1994.01.