Development of the dentin-repairing therapy regulating the calcium-sensing receptor

• Project/Area Number: 26670825
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Conservative dentistry
• Research Institution: Kyushu University
• Principal Investigator: MAEDA HIDEFUMI 九州大学, 歯学研究院, 教授 (10284514)
• Co-Investigator(Kenkyū-buntansha): 赤峰 昭文 九州大学, 歯学研究院, 教授 (00117053) ; 和田 尚久 九州大学, 大学病院, 教授 (60380466) ; 門野内 聡 九州大学, 歯学研究院, 助教 (30609558) ; 友清 淳 九州大学, 大学病院, 講師 (20507777)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
• Keywords: カルシウム感知受容体 / 歯髄幹細胞 / 象牙芽細胞分化 / アクリル系レジン / デンチンブリッジ / カルシウム / ストロンチウム / リン酸化ERK / TGF-beta-ig-h3 / ヒト歯髄細胞 / カルシウムチャネル / 歯髄細胞

Outline of Final Research Achievements

In this study, we looked at the positive function of the signal through calcium sensing receptor (CaSR) on hard tissue formation. We therefore aimed at developing the direct dental pulp capping material that would not induce pulp tissue necrosis beneath the pulp exposed area, but promote dentin bridge formation when it would be applied to pulp exposed portion. First we have obtained human dental pulp stem cells that showed the multi-differentiation properties and expressed mesenchymal stem cell markers. Next when this cell was treated with calcium, a potent CaSR stimulator, we found that it led to the odontoblastic differentiation. Thus, we produced the hydroxyapatite-containing acrylic resin, and then applied it to the pulp exposed model rat. Consequently, we found that this material could induce dentin bridge formation beneath the application area without triggering the necrosis of pulp tissue

Research Products

• [Journal Article] Glial cell line-derived neurotrophic factor from human periodontal ligament cells treated with proinflammatory cytokines promotes neurocytic differentiation of PC12 cells. (2017)
  • Author(s): Yoshida S, Yamamoto N, Wada N, Tomokiyo A, Hasegawa D, Hamano S, Mitarai H, Monnouchi S, Yuda A, Maeda H.
  • Journal Title: J Cell Biochem. Volume: 118 Issue: 4 Pages: 699-708
  • DOI: 10.1002/jcb.25662
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transforming growth factor-β-induced gene product-h3 inhibits odontoblastic differentiation of dental pulp cells. (2017)
  • Author(s): Serita S, Tomokiyo A, Hasegawa D, Hamano S, Sugii H, Yoshida S, Mizumachi H, Mitarai H, Monnouchi S, Wada N, Maeda H.
  • Journal Title: Arch Oral Biol. Volume: 78 Pages: 135-143
  • DOI: 10.1016/j.archoralbio.2017.02.018
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Grp78 is critical for amelogenin-induced cell migration in a multipotent clonal human periodontal ligament cell line. (2016)
  • Author(s): Toyoda K, Fukuda T, Sanui T*, Tanaka U, Yamamichi K, Atomura R, Maeda H, Tomokiyo A, Taketomi T, Uchiumi T, Nishimura F
  • Journal Title: Journal of Cellular Physiology Volume: 231 Issue: 2 Pages: 414-427
  • DOI: 10.1002/jcp.25087
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Semaphorin 3A Induces Odontoblastic Phenotype in Dental Pulp Stem Cells. (2016)
  • Author(s): Yoshida S, Wada N, Hasegawa D, Miyaji H, Mitarai H, Tomokiyo A, Hamano S, Maeda H.
  • Journal Title: Journal of Dental Research Volume: 95 Issue: 11 Pages: 1282-1290
  • DOI: 10.1177/0022034516653085
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Benzo[a]pyrene/aryl hydrocarbon receptor signaling inhibits osteoblastic differentiation and collagen synthesis of human periodontal ligament cells. (2016)
  • Author(s): Monnouchi S, Maeda H, Yuda A, Serita S, Wada N, Tomokiyo A, Akamine A.
  • Journal Title: J Periodontal Res. Volume: 51 Issue: 6 Pages: 779-788
  • DOI: 10.1111/jre.12355
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Periodontal Ligament Stem Cells in Regenerative Dentistry for Periodontal Tissues. (2016)
  • Author(s): Tomokiyo A, Wada N, Hamano S, Hasegawa D, Sugii H, Yoshida S, Maeda H.
  • Journal Title: J Stem Cell Res Ther Volume: 118 Pages: 00019-00019
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Mechanical induction of interleukin-11 regulates osteo/cementoblastic differentiation of human periodontal ligament stem/progenitor cells. (2015)
  • Author(s): Monnouchi S, Maeda H, Yuda A, Hamano S, Wada N, Tomokiyo A, Koori K, Sugii H, Serita S, Akamine A
  • Journal Title: J Periodontal Res Volume: 50 Issue: 8 Pages: 231-239
  • DOI: 10.1111/iej.12361
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Effect of CTGF/CCN2 on osteo/cementoblastic and fibroblastic differentiation of a human periodontal ligament stem/progenitor cell line. (2015)
  • Author(s): Yuda A, Maeda H, Fujii S, Monnouchi S, Yamamoto N, Wada N, Koori K, Tomokiyo A, Hamano S, Hasegawa D, Akamine A
  • Journal Title: J Cell Physiol. Volume: 230 Issue: 1 Pages: 150-159
  • DOI: 10.1002/jcp.24693
  • Peer Reviewed
• [Journal Article] Quest for the development of tooth root/periodontal ligament complex by tissue engineering. (2014)
  • Author(s): Maeda H, Akamine A
  • Journal Title: Integr Mol Med Volume: 1 Pages: 22-25
  • Peer Reviewed
• [Presentation] Transgelin mediates TGF-beta1-induced human periodontal ligament cell proliferation. (2017)
  • Author(s): Hiromi Mitarai, Naohisa Wada, Daigaku Hasegawa, Shinichiro Yoshida, Mai Sonoda, Atsushi Tomokiyo, Sayuri Hamano, Hidefumi Maeda.
  • Organizer: 95th General Session & Exhibition of the IADR.
  • Place of Presentation: Moscone West, San Francisco, USA.
  • Year and Date: 2017-03-22
  • Int'l Joint Research
• [Presentation] Transgelin mediates the proliferation of human periodontal ligament cells induced by TGF-β1 (2017)
  • Author(s): Hiromi Mitarai, Naohisa Wada, Daigaku Hasegawa, Shinichiro Yoshida, Mai Sonoda, Atsushi Tomokiyo, Sayuri Hamano, Suguru Serita, Hiroyuki Mizumachi, Hidefumi Maeda.
  • Organizer: Kyudai Oral Bioscience 2017
  • Place of Presentation: Kyushu University
  • Int'l Joint Research
• [Presentation] 根管治療ならびに修復処置関連溶液によって誘導されるMineral Trioxide Aggregateの色調変化に関する比較分析 (2016)
  • Author(s): 友清淳、和田尚久、濱野さゆり、長谷川大学、杉井英樹、吉田晋一郎、芹田俊、御手洗裕美、水町博之、前田英史
  • Organizer: 第14５回日本歯科保存学会秋季学術大会
  • Place of Presentation: キッセイ文化ホール
  • Year and Date: 2016-10-27
• [Presentation] 紫外線照射が歯内疾患関連細菌および歯髄細胞に及ぼす影響 (2016)
  • Author(s): 原口 晃、吉田晋一郎、竹下正章、角 保徳、西村英紀、前田英史、和田尚久
  • Organizer: 第14５回日本歯科保存学会秋季学術大会
  • Place of Presentation: キッセイ文化ホール
  • Year and Date: 2016-10-27
• [Presentation] R-spondin2が未分化なヒト歯根膜細胞の線維芽細胞様分化に及ぼす影響． (2016)
  • Author(s): 園田麻衣、長谷川大学、和田尚久、吉田晋一郎、御手洗裕美、友清淳、濱野さゆり、前田英史．
  • Organizer: 第14５回日本歯科保存学会秋季学術大会
  • Place of Presentation: キッセイ文化ホール
  • Year and Date: 2016-10-27
• [Presentation] LPS刺激歯根膜細胞におけるオートファジーの役割． (2016)
  • Author(s): 萩尾佳那子、大野純、山口真広、瀬野恵衣、山田和彦、米田雅裕、前田英史、廣藤卓雄
  • Organizer: 第14５回日本歯科保存学会秋季学術大会
  • Place of Presentation: キッセイ文化ホール
  • Year and Date: 2016-10-27
• [Presentation] 歯根膜および皮膚由来ヒト人工多能性幹細胞（iPSC）を用いた神経堤細胞様細胞の樹立とキャラクタリゼーション (2016)
  • Author(s): 友清淳、和田尚久、濱野さゆり、長谷川大学、杉井英樹、吉田晋一郎、前田英史．
  • Organizer: 第23回日本歯科医学会総会
  • Place of Presentation: 福岡サンパレス
  • Year and Date: 2016-10-21
• [Presentation] ヒト歯髄細胞の老化と象牙芽細胞様分化におよぼすTNF-αの影響について (2016)
  • Author(s): 野津葵、友清淳、長谷川大学、濱野さゆり、吉田晋一郎、杉井英樹、芹田俊、水町博之、御手洗裕美、和田尚久、前田英史
  • Organizer: 第３７回日本歯内療法学会学術大会
  • Place of Presentation: ウインクあいち
  • Year and Date: 2016-07-23
• [Presentation] Semaphorin 3A Induces Odontoblastic Phenotype in Dental Pulp Stem Cells. (2016)
  • Author(s): S. Yoshida, N. Wada, D. Hasegawa, A. Tomokiyo, S. Hamano, H. Mitarai, H. Sugii, H. Maeda.
  • Organizer: 94th General Session & Exhibition of the IADR
  • Place of Presentation: COEX Convention Center, Seuol, Republic of Korea.
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Directing Human iPS Cells Toward PDL Stem Cells. (2016)
  • Author(s): S. Hamano, A. Tomokiyo, N. Wada, D. Hasegawa, H. Sugii, S. Yoshida, S. Serita, H. Mizumachi, H. Mitarai, H. Maeda.
  • Organizer: 94th General Session & Exhibition of the IADR
  • Place of Presentation: COEX Convention Center, Seuol, Republic of Korea.
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] Identification of a Novel Periodontal Ligament Stem Cell Marker. (2016)
  • Author(s): D. Hasegawa, N. Wada, S. Hamano, A. Tomokiyo, S. Yoshida, H. Mitarai, M. Sonoda, H. Sugii, H. Maeda.
  • Organizer: 94th General Session & Exhibition of the IADR
  • Place of Presentation: COEX Convention Center, Seuol, Republic of Korea.
  • Year and Date: 2016-06-22
  • Int'l Joint Research
• [Presentation] 歯髄細胞におけるTGFbetaig-h3の発現および機能について． (2016)
  • Author(s): 芹田俊、友清淳、長谷川大学、濱野さゆり、杉井英樹、吉田晋一郎、水町博之、御手洗裕美、和田尚久、前田英史．
  • Organizer: 第144回日本歯科保存学会春季学術大会
  • Place of Presentation: 栃木県総合文化センター
  • Year and Date: 2016-06-09
• [Presentation] Semaphorin 3A induces odontoblastic phenotype in dental pulp stem cells. (2016)
  • Author(s): Shinichiro Yoshida, Naohisa Wada, Daigaku Hasegawa, Atsushi Tomokiyo, Sayuri Hamano, Hiromi Mitarai, Suguru Serita, Hiroyuki Mizumachi, Hidefumi Maeda
  • Organizer: Kyudai Oral Bioscience 2016
  • Place of Presentation: Kyushu University
  • Year and Date: 2016-02-27
  • Int'l Joint Research
• [Presentation] iPS細胞由来の歯根膜幹細胞様細胞の樹立 (2016)
  • Author(s): 濱野さゆり、友清淳、和田尚久、長谷川大学、杉井英樹、吉田晋一郎、芹田俊、水町博之、御手洗裕美、 前田英史
  • Organizer: 第144回日本歯科保存学会春季学術大会
  • Place of Presentation: 栃木県総合文化センター
• [Presentation] MESTはヒト歯根膜幹細胞における幹細胞特性の維持に関与する． (2016)
  • Author(s): 長谷川大学、和田尚久、濱野さゆり、友清淳、吉田晋一郎、御手洗裕美、前田英史．
  • Organizer: 第144回日本歯科保存学会春季学術大会
  • Place of Presentation: 栃木県総合文化センター
• [Presentation] Collaborative Activity of CTGF/CCN2 and TGF-β1 on Osteogenesis and Fibrogenesis (2015)
  • Author(s): A. Yuda, H. Maeda, S. Fujii, S. Monnouchi, N. Wada, A. Tomokiyo, S. Hamano, D. Hasegawa, H. Sugii, S. Yoshida, A. Akamine.
  • Organizer: 93rd General Session & Exhibition of the IADR
  • Place of Presentation: Boston
  • Year and Date: 2015-03-11 – 2015-03-14
• [Presentation] Effect of β2 Adrenergic Receptor on Human Periodontal Ligament Cells (2015)
  • Author(s): S. Hamano, H. Maeda, D. Hasegawa, S. Monnouchi, N. Wada, A. Tomokiyo, A. Yuda, H. Sugii, S. Yoshida, A. Akamine.
  • Organizer: 93rd General Session & Exhibition of the IADR
  • Place of Presentation: Boston
  • Year and Date: 2015-03-11 – 2015-03-14
• [Presentation] The Effects of Wnt5a on Human Periodontal Ligament Cells. (2015)
  • Author(s): D. Hasegawa, N. Wada, H. Maeda, S. Yoshida, H. Mitarai, A. Tomokiyo, S. Monnouchi, S. Hamano, A. Yuda, A. Akamine.
  • Organizer: 93rd General Session & Exhibition of the IADR
  • Place of Presentation: Boston
  • Year and Date: 2015-03-11 – 2015-03-14
• [Presentation] 骨芽細胞様分化におけるActivin Aの作用は前骨芽細胞と歯根膜細胞とで相反する (2014)
  • Author(s): 杉井英樹、前田英史、友清淳、和田尚久、門野内聡、長谷川大学、濱野さゆり、祐田明香、吉田晋一郎、赤峰昭文
  • Organizer: 第141回日本歯科保存学会秋季学術大会
  • Place of Presentation: 山形テルサ
  • Year and Date: 2014-10-30 – 2014-10-31
• [Presentation] Wnt5aはRor2-JNKシグナルを介してヒト歯根膜幹細胞株の骨芽細胞様分化を抑制する (2014)
  • Author(s): 長谷川大学、和田尚久、前田英史、吉田晋一郎、御手洗裕美、門野内聡、濱野さゆり、祐田明香、赤峰昭文
  • Organizer: 第141回日本歯科保存学会秋季学術大会
  • Place of Presentation: 山形テルサ
  • Year and Date: 2014-10-30 – 2014-10-31
• [Presentation] 2アドレナリン受容体の作動薬および非作動薬がヒト歯根膜細胞に及ぼす影響 (2014)
  • Author(s): 濱野さゆり、前田英史、長谷川大学、和田尚久、友清淳、門野内聡、祐田明香、杉井英樹、赤峰昭文
  • Organizer: 第140回日本歯科保存学会春季学術大会
  • Place of Presentation: 滋賀県立芸術劇場びわ湖ホール
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] Wnt5aはTGF1を介してヒト歯根膜細胞のコラーゲン線維形成を促進する (2014)
  • Author(s): 長谷川大学、和田尚久、前田英史、吉田晋一郎、門野内聡、御手洗裕美、濱野さゆり、祐田明香、赤峰昭文
  • Organizer: 第140回日本歯科保存学会春季学術大会
  • Place of Presentation: 滋賀県立芸術劇場びわ湖ホール
  • Year and Date: 2014-06-19 – 2014-06-20
• [Presentation] Semaphorin3Aがヒト歯髄幹細胞による硬組織形成に及ぼす影響 (2014)
  • Author(s): 吉田晋一郎、和田尚久、前田英史、門野内聡、長谷川大学、御手洗裕美、濱野さゆり、祐田明香、杉井英樹、赤峰昭文
  • Organizer: 第140回日本歯科保存学会春季学術大会
  • Place of Presentation: 滋賀県立芸術劇場びわ湖ホール
  • Year and Date: 2014-06-19 – 2014-06-20
• [Book] Frontiers in Stem Cell and Regenerative Medicine Research (2016)
  • Author(s): Tomokiyo A, Wada N, Maeda H.
  • Total Pages: 294
  • Publisher: Bentham Science
• [Book] Dental Stem Cells. (2016)
  • Author(s): Wada N, Tomokiyo A, Maeda H.
  • Total Pages: 309
  • Publisher: Springer
• [Book] Frontiers in Stem Cell and Regenerative Mudicine Research (2016)
  • Author(s): Tomokiyo A, Wada N, Maeda H.
  • Publisher: Bentham Science