Generation of a compound that has the potential to induce the formation of PDLSCs using iPS- and genome-based drug discovery technology.

• Project/Area Number: 18K19651
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 57:Oral science and related fields
• Research Institution: Kyushu University
• Principal Investigator: Atsushi Tomokiyo 九州大学, 大学病院, 講師 (20507777)
• Co-Investigator(Kenkyū-buntansha): 前田 英史 九州大学, 歯学研究院, 教授 (10284514) ; 長谷川 大学 九州大学, 大学病院, 助教 (20757992) ; 吉田 晋一郎 九州大学, 大学病院, 助教 (30778866) ; 濱野 さゆり 九州大学, 歯学研究院, 助教 (40757978) ; 和田 尚久 九州大学, 大学病院, 教授 (60380466) ; 杉井 英樹 九州大学, 大学病院, 助教 (80802280)
• Project Period (FY): 2018-06-29 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000)
• Keywords: 歯周組織再生 / 歯根膜幹細胞 / 神経堤細胞 / 低分子化合物 / 歯周組織再生医療 / iPS細胞 / ゲノム創薬 / 再生医療 / SNP / 幹細胞賦活化 / 再生療法 / iPS創薬 / 歯根膜組織再生 / ヒト由来iPS細胞 / iPS由来神経堤細胞

Outline of Final Research Achievements

Periodontal ligament stem cells (PDLSCs) are known to be of great importance in the regeneration of periodontal tissues, however they are extremely rare population. Our research aim is developing a compound that induces the differentiation of neural crest cells (NC) to PDLSCs. Our recent study demonstrated that human NC line cultured with periodontal ligament cell-derived extra cellular matrix and the compound X increased the expression of periodontal ligament-related genes, such as COL-1, OPN, FBN1, and POSTN. Our study suggested that the compound X would have the potential to induce the differentiation of NC into PDLSCs and it may become a new medicine for the regeneration of destructed periodontal tissues.

Academic Significance and Societal Importance of the Research Achievements

現在までに歯周組織再生療法に用いられる薬剤として、いくつかのタンパク製剤が知らているが、それらは高価であり、またロット間でのばらつきも指摘されている。そこで申請者らが本研究にて着目したCompoundXは低分子化合物であることから、人工的に大量生産が可能であり、また科学的修飾により安定性や安全性を高めることができる。したがって、本研究結果は、現在用いられている歯周組織再生療法薬にとってかわる可能性を有していることから、本研究の持つ社会的意義は高いと考えられる。

Research Products

• [Journal Article] Generation of biohybrid implants using a multipotent human periodontal ligament cell line and bioactive core materials. (2021)
  • Author(s): Ono T, Tomokiyo A, Ipposhi K, Yamashita K, Alhasan MA, Miyazaki Y, Kunitomi Y, Tsuchiya A, Ishikawa K, Maeda H.
  • Journal Title: J Cell Physiol. Volume: - Issue: 9 Pages: 30336-30336
  • DOI: 10.1002/jcp.30336
  • NAID: 120007193918
  • Peer Reviewed
• [Journal Article] Functions of beta2‐adrenergic receptor in human periodontal ligament cells (2020)
  • Author(s): Hamano Sayuri、Tomokiyo Atsushi、Hasegawa Daigaku、Yuda Asuka、Sugii Hideki、Yoshida Shinichiro、Mitarai Hiromi、Wada Naohisa、Maeda Hidefumi
  • Journal Title: Journal of Cellular Biochemistry Volume: 121 Issue: 12 Pages: 4798-4808
  • DOI: 10.1002/jcb.29706
  • Peer Reviewed / Open Access
• [Journal Article] Possible function of GDNF and Schwann cells in wound healing of periodontal tissue. (2020)
  • Author(s): Itoyama T, Yoshida S, Tomokiyo A, Hasegawa D, Hamano S, Sugii H, Ono T, Fujino S, Maeda H.
  • Journal Title: J Periodont Res. Volume: 55 Issue: 6 Pages: 830-839
  • DOI: 10.1111/jre.12774
  • Peer Reviewed
• [Journal Article] Insight into the Role of Dental Pulp Stem Cells in Regenerative Therapy. (2020)
  • Author(s): Yoshida S, Tomokiyo A, Hasegawa D, Hamano S, Sugii H, Maeda H.
  • Journal Title: Biology-Basel. Volume: 9 Issue: 7 Pages: 160-160
  • DOI: 10.3390/biology9070160
  • Peer Reviewed / Open Access
• [Journal Article] MEST Regulates the Stemness of Human Periodontal Ligament Stem Cells (2020)
  • Author(s): Daigaku Hasegawa, Kana Hasegawa, Hiroshi Kaneko, Shinichiro Yoshida, Hiromi Mitarai, Mai Arima, Atsushi Tomokiyo, Sayuri Hamano, Hideki Sugii, Naohisa Wada, Tamotsu Kiyoshima, Hidefumi Maeda
  • Journal Title: Stem Cells International Volume: - Pages: 1-15
  • DOI: 10.1155/2020/9672673
  • Peer Reviewed / Open Access
• [Journal Article] Expression and function of dopamine in odontoblasts (2019)
  • Author(s): Fujino Shoko、Hamano Sayuri、Tomokiyo Atsushi、Itoyama Tomohiro、Hasegawa Daigaku、Sugii Hideki、Yoshida Shinichiro、Washio Ayako、Nozu Aoi、Ono Taiga、Wada Naohisa、Kitamura Chiaki、Maeda Hidefumi
  • Journal Title: Journal of Cellular Physiology Volume: 235 Issue: 5 Pages: 4376-4387
  • DOI: 10.1002/jcp.29314
  • NAID: 120006892319
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Periodontal Ligament Stem Cells: Regenerative Potency in Periodontium (2019)
  • Author(s): Tomokiyo Atsushi、Wada Naohisa、Maeda Hidefumi
  • Journal Title: Stem Cells and Development Volume: 28 Issue: 15 Pages: 974-985
  • DOI: 10.1089/scd.2019.0031
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] R-spondin 2 promotes osteoblastic differentiation of immature human periodontal ligament cells through the Wnt/β-catenin signaling pathway (2018)
  • Author(s): Arima Mai、Hasegawa Daigaku、Yoshida Shinichiro、Mitarai Hiromi、Tomokiyo Atsushi、Hamano Sayuri、Sugii Hideki、Wada Naohisa、Maeda Hidefumi
  • Journal Title: Journal of Periodontal Research Volume: 54 Issue: 2 Pages: 143-153
  • DOI: 10.1111/jre.12611
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Detection, Characterization, and Clinical Application of Mesenchymal Stem Cells in Periodontal Ligament Tissue. (2018)
  • Author(s): Tomokiyo A, Yoshida S, Hamano S, Hasegawa D, Sugii H, Maeda H.
  • Journal Title: Stem Cells Int. Volume: 26 Pages: 1-9
  • DOI: 10.1155/2018/5450768
  • Peer Reviewed / Open Access
• [Presentation] Develpoment of a new biohybridimplant system applying 3D-printing technology (2020)
  • Author(s): T. Ono, A. Tomokiyo, D. Hasegawa, S. Hamano, S. Yoshida, H. Sugii, S. Fujino, T. Itoyama, H. Maeda.
  • Organizer: The 98th General Session & Exhibition of the IADR
  • Int'l Joint Research
• [Presentation] Possibility of Schwann cells to contribute to periodontal wound healing． (2020)
  • Author(s): T. Itoyama, S. Yoshida, A. Tomokiyo, D. Hasegawa, S. Hamano1, H. Sugii, T. Ono, S. Fujino, H. Maeda．
  • Organizer: The 98th General Session & Exhibition of the IADR
  • Int'l Joint Research
• [Presentation] レジン系、バイオガラス系およびシリコン系根管充填用シーラーのヒト歯根膜幹細胞株に対する細胞親和性比較 (2020)
  • Author(s): 友清 淳、長谷川 大学、小野 太雅、一法師 啓太、山下 梢、M Anas Alhasan、濱野さゆり、杉井 英樹、吉田 晋一郎、前田 英史．
  • Organizer: 第152回日本歯科保存学会春季学術大会
• [Presentation] フェノール系貼薬剤は硬化後のWhite Mineral Trioxide Aggregateの崩壊および色調変化を誘導する． (2020)
  • Author(s): 友清 淳、山下 梢、小野 太雅、一法師 啓太、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41回日本歯内療法学会学術大会（誌上開催
• [Presentation] 102. sFRP1は歯髄細胞の象牙芽細胞様分化を誘導し、デンティンブリッジ形成を促進する (2020)
  • Author(s): 一法師 啓太、友清 淳、小野 太雅、山下梢、長谷川 大学、濱野 さゆり、吉田 晋一郎、杉井 英樹、前田 英史
  • Organizer: 第41回日本歯内療法学会学術大会
• [Presentation] Effects of TNF-a. on Senescent human dental pulp cells. (2019)
  • Author(s): Aoi Nozu, Sayuri Hamano ,Atsushi Tomokiyo, Daigaku Hasegawa, Shinichiro Yoshida, Hideki Sugii,Hiromi Mitarai, Keita Ipposhi, Naohisa Wada, Hidefumi Maeda.
  • Organizer: Kyudai Oral Bioscience＆OBT Research Center Joint International Symposium
  • Int'l Joint Research
• [Presentation] Effects of dopamine on odontoblastic differentiation through PKA signaling. (2019)
  • Author(s): Shoko Fujino, Hamano Sayuri, Atsushi Tomokiyo, Daigaku Hasegawa, Shinichiro Yoshida, Hideki Sugii, Ayako Washio, Hiromi Mitarai, Naohisa Wada, Chiaki Kitamura, Hidefumi Maeda.
  • Organizer: The 97th General Session & Exhibition of the IADR
  • Int'l Joint Research
• [Presentation] Activin Aが有する二極性の細胞分化誘導能に関する分子機構の解明． (2019)
  • Author(s): 杉井英樹、友清淳、濱野さゆり、長谷川大学、吉田晋一郎、Mhd Safwan Albougha、前田英史
  • Organizer: 日本歯科保存学会2019年度春季学術大会．
• [Book] Precision Medicine. (2019)
  • Author(s): 友清 淳
  • Publisher: 北隆館
• [Book] BIO Clinica. (2019)
  • Author(s): 友清 淳
  • Publisher: 北隆館