Challenge to the development of new treatments applying the enhancement of periodontal tissue regeneration by controlling stem cell aging

• Project/Area Number: 18H02982
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57040:Regenerative dentistry and dental engineering-related
• Research Institution: Osaka University
• Principal Investigator: Kitamura Masahiro 大阪大学, 歯学研究科, 准教授 (10243247)
• Co-Investigator(Kenkyū-buntansha): 竹立 匡秀 大阪大学, 歯学部附属病院, 講師 (60452447) ; 村上 伸也 大阪大学, 歯学研究科, 教授 (70239490) ; 山下 元三 大阪大学, 歯学部附属病院, 講師 (90524984)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,550,000 (Direct Cost: ¥13,500,000、Indirect Cost: ¥4,050,000); Fiscal Year 2020: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000)
• Keywords: 歯周組織再生 / ステムセルエイジング / 歯根膜細胞

Outline of Final Research Achievements

In this study, elucidating the aging mechanism of periodontal ligament stem cells at the molecular level, we investigated the possibility that aging control of stem cells enhances the effect of periodontal tissue regeneration. As a result, the analysis of the miRNA expression profile during the aging process of periodontal ligament cells revealed a relationship between the increased expression of miRNA-137 and the genes involved in delaying the processing of damaged mitochondria in the aged periodontal ligament cells. Furthermore, since a significant decrease in the expression of these genes was observed in periodontal ligament cells into which artificial microRNA-mimicking strands having a sequence homologous to miRNA-137 were introduced, it was suggested that the control of stem cell aging may enhance the regeneration effect of periodontal tissue.

Academic Significance and Societal Importance of the Research Achievements

本研究により、miRNA-137と損傷ミトコンドリアの処理過程の遅延に関与する遺伝子群との関連性が明らかとなり、幹細胞のエネルギー代謝の中心となるミトコンドリア代謝の調節経路の異常が歯根膜細胞のステムセルエイジングに関与する可能性が示唆された。そして、miRNA-137などの人工microRNA模倣鎖を導入した歯根膜細胞において、損傷ミトコンドリアの標識と隔離膜への囲い込みに関与する遺伝子群の有意な発現減少が認められたことから、これらのmiRNAsを標的とするマイトファジー制御を基盤とする核酸治療薬がステムセルエイジング制御に有用である可能性が示唆された。

Research Products

• [Journal Article] Association of periodontal disease with atherosclerosis in 70-year-old Japanese older adults (2020)
  • Author(s): Kitamura M, Ikebe K, Kamide K, Gondo Y, Yamashita M, Takedachi M, Nozaki T, Fujihara C, Yamada S, Kashiwagi Y, Miki K, Iwayama T, Hatta K, Mihara Y, Kurushima Y et al
  • Journal Title: Odontology Volume: 109 Issue: 2 Pages: 506-513
  • DOI: 10.1007/s10266-020-00567-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Clinical Outcome of Periodontal Tissue Regeneration Therapy by Administration of Basic Fibroblast Growth Factor (FGF-2) (2020)
  • Author(s): 沢田啓吾 北村正博 長谷川詩織 森本千晶 平井麻絵 今井昂 川嵜公輔 橋本康樹 麻生桃子 辻井翔一 野田亜利紗 花田滉輔 政近健司 藤田翔子 鈴木美麻 八木寛子 池上久仁子 山本智美 森健太 中村友美 小笹匡雄 北垣次郎太 岩山智明 柏木陽一郎 藤原千春 三木康史 竹立匡秀 山下元三 野崎剛徳 村上伸也
  • Journal Title: The Japanese Journal of Conservative Dentistry Volume: 63 Issue: 3 Pages: 219-227
  • DOI: 10.11471/shikahozon.63.219
  • NAID: 130007871208
  • ISSN: 0387-2343, 2188-0808
  • Peer Reviewed / Open Access
• [Presentation] 歯根膜細胞の分化過程におけるCGRPの機能解析 (2020)
  • Author(s): 竹下登、三木康史、山下元三、北村正博、村上伸也
  • Organizer: 第63回秋季日本歯周病学会学術大会
• [Presentation] Genetic and Environmental Factors on Periodontitis in Elderly Twins. (2020)
  • Author(s): Ikegami K, Yamashita M, Miki K, Nishikawa A, Hashimoto K, Morikawa T, Takeshita N, Ikebe K, Kitamura M and Murakami S.
  • Organizer: 106th Annual Meeting American Academy of Periodontology
  • Int'l Joint Research / Invited
• [Presentation] 日本人侵襲性歯周炎の疾患関連遺伝子Paraxonase-1の機能解析 (2020)
  • Author(s): 桝本梨沙、藤原千春、松本昌大、山本優、北垣次郎太、北村正博、村上伸也
  • Organizer: 第153回日本歯科保存学会2020年度秋季学術大会
• [Presentation] Identification of genetic riskfactors of aggressive periodontitis in the Japanese population (2020)
  • Author(s): T Nantakeeratipat、C Fujihara、M Matsumoto、R Masumoto、J Kitagaki、Y Yamamoto、M Kinoshita、M Kitamura、S Murakami
  • Organizer: 第63回秋季日本歯周病学会学術大会
• [Presentation] Roles of HSPs for Type 1 Collagen Synthesis in HPDL Cells (2020)
  • Author(s): A. Nishikawa, M.Yamashita, M. Suzuki, K. Ikegami, T. Nakamura, K. Hashimoto, T. Morikawa, M. Kitamura, S. Murakami
  • Organizer: 98th General Session & Exhibition of the IADR
  • Int'l Joint Research
• [Presentation] 大阪大学歯学部附属病院（口腔治療・歯周科）における塩基性線維芽細胞（FGF-2）製剤を用いた歯周組織再生療法の治療実績 (2019)
  • Author(s): 長谷川詩織、北村正博、今井昴、川嵜公輔、橋本康樹、花田滉輔、麻生桃子、野田亜利紗、辻井翔一、政近健司、藤田翔子、鈴木美麻、平井麻絵、森本千晶、八木寛子、池上久仁子、沢田啓吾、中村友美、岩山智明、柏木陽一郎、藤原千春、三木康史、竹立匡秀、山下元三、野崎剛徳、村上伸也
  • Organizer: 第151回秋季日本保存学会
• [Presentation] MiR-34a Regutates Stem Cell Aging in Periodontal ligament Stem Cells. (2019)
  • Author(s): Ikegami K, Yamashita M, Suzuki M, Nishikawa A, Hashimoto K, Nakamura T, Miki K, Yanagita M, Kitamura M, Murakami S.
  • Organizer: 13th Asian Pacific Society of Periodontology Meeting
  • Int'l Joint Research
• [Presentation] Analysis of Mitophagy in Senescent HPDL Cell. (2019)
  • Author(s): Yamashita M, Suzuki M, Ikegam K, Nakamura T, Nishikawa A, Hashimoto K, Morikawa T, Miki K, Yanagita M, Kitamura M, Shinya Murakami.
  • Organizer: 13th Asian Pacific Society of Periodontology Meeting
  • Int'l Joint Research
• [Presentation] 老化ヒト歯根膜細胞における活性酸素産生に及ぼすマイトファジーの役割 (2019)
  • Author(s): 鈴木美麻，山下元三，池上久仁子，中村友美，西川有彩，橋本康樹，北村正博，村上伸也
  • Organizer: 日本歯科保存学会春季学術大会（第150回）
• [Presentation] NMN Improves the Accumulation of ROS in Senescent HPDL Cells (2019)
  • Author(s): Hashimoto K, Yamashita M, Suzuki M, Ikegami K, Nakamura T, Nishikawa A, Morikawa T, Kitamura M, Murakami S
  • Organizer: 4th Meeting of the International Association for Dental Research Asia Pacific Region 2019
  • Int'l Joint Research
• [Presentation] Activation of HSPs Ameliorates the Collagen Production in HPDL Cells (2019)
  • Author(s): Nishikawa A, Yamashita M, Suzuki M, Ikegami K, Nakamura T, Hashimoto K, Morikawa T, Kitamura M, Murakami S
  • Organizer: 4th Meeting of the International Association for Dental Research Asia Pacific Region 2019
  • Int'l Joint Research
• [Presentation] Therapeutic efficacy and stem cell characteristics association in stem cell transplantation therapy (2019)
  • Author(s): Takedachi M, Sawada K, Morimoto C, Hirai A, Shimomura J, Kawasaki K, Iwayama T, Kitamura M, Murakami S
  • Organizer: 13th Asian Pacific Society of Periodontology Meeting
  • Int'l Joint Research
• [Presentation] 歯周組織再生剤「リグロス」の開発から学んだ歯科用薬剤開発の難しさ (2018)
  • Author(s): 北村正博
  • Organizer: 第36回日本骨代謝学会
  • Invited
• [Presentation] Stem cell therapy for periodontal regeneration (2018)
  • Author(s): Masahide Takedachi
  • Organizer: 104th American Academy of Periodontology
  • Int'l Joint Research / Invited
• [Presentation] Evaluation of periodontal tissue regeneration by transplantation of adipose tissue-derived multi-lineage progenitor cells in a clinical study (2018)
  • Author(s): Masahide Takedachi, Shinya Murakami
  • Organizer: 5th TERMIS World Congress
  • Int'l Joint Research / Invited
• [Presentation] タバコ煙の長期曝露が歯肉線維芽細胞の細胞機能に及ぼす影響 (2018)
  • Author(s): 辰巳真理、柳田学、長谷川詩織、鈴木美麻、池上久仁子、山下元三、北村正博、村上伸也
  • Organizer: 第61回春季日本歯周病学会
• [Presentation] Clinical Evaluation of Periodontal Tissue Regeneration by ADMPC Transplantation (2018)
  • Author(s): Masahide Takedachi, Keigo Sawada, Chiaki Morimoto, Satomi Yamamoto, Asae Hirai, Junpei Shimomura, Yuki Narukawa, Yoichiro Kashiwagi, Tomoaki Iwayama, Masahiro Kitamura, Shinya Murakami
  • Organizer: 96th IADR
  • Int'l Joint Research
• [Presentation] Impairment of mitophagy in senescent HPDL cells (2018)
  • Author(s): Mio SUZUKI, Motozo YAMASHITA, Kuniko IKEGAMI, Tomomi NAKAMURA, Koji MIKI, Manabu YANAGITA, Masahiro KITAMURA, Shinya MURAKAMI
  • Organizer: 96th IADR
  • Int'l Joint Research
• [Presentation] Optical dissection of the mitophagy dynamics in HPDL cells (2018)
  • Author(s): Motozo Yamashita, Mio Suzuki, Kuniko Ikegami, Tomomi Nakamura, Arisa Nishikawa, Koji Miki, Manabu Yanagita, Masahiro Kitamura, Shinya Murakami
  • Organizer: AAP 104th Annual Meeting
  • Int'l Joint Research
• [Presentation] Senescence-associated miR-34a suppress osteoblastic differentiation in periodontal stem cell (2018)
  • Author(s): Kuniko Ikegami, Motozo Yamashita, Mio Suzuki, Arisa Nishikawa, Tomomi Nakamura, Koji Miki, Manabu Yanagita, Masahiro Kitamura, Shinya Murakami
  • Organizer: 66th JADR
  • Int'l Joint Research