Analysis of stem-cell aging by targeting miR-34a-SATB2 axis

• Project/Area Number: 18K17064
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57030:Conservative dentistry-related
• Research Institution: Osaka University
• Principal Investigator: Ikegami Kuniko 大阪大学, 歯学部附属病院, 医員 (80779116)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 歯周病 / 老化 / 歯根膜細胞 / miR-34a / SATB2 / ステムセルエイジング / micro RNA-34a / 幹細胞 / 細胞老化

Outline of Final Research Achievements

Periodontitis is a chronic inflammatory disease characterized by the destruction of periodontal tissue, and its prevalence increases with age. MicroRNAs (miRNAs) are stress-responsive small RNAs that have been reported to be involved in the regulation of senescence and lifespan in small animals, suggesting the involvement of cellular senescence and stem cell aging. We found that miR-34a is strongly expressed in senescent periodontal cells and targets SATB2 (a gene that promotes hard tissue formation). miR-34a-transfected cells and SATB2- knocked down cells showed decreased expression of calcification-related genes under the calcification-induced culture. This study demonstrates that regulation of SATB2 expression by miR-34a in senescent periodontal ligament cells is partly responsible for stem-cell aging, loss of stem-cellness, of the periodontal ligament cells.

Academic Significance and Societal Importance of the Research Achievements

歯根膜は、歯周組織の修復・再生にとり重要な組織である。老化歯根膜細胞においてはmiRNA-34の発現が増加し、その標的遺伝子であるSATB2（硬組織形成を促進する遺伝子）の発現は減少していたことから、miR-34aがSATB2を調節制御していることが示唆された。miR-34aを遺伝子導入した細胞株、SATB2を欠失させた細胞株において石灰化関連遺伝子の発現は減少しており、miR-34a-SATB2経路が歯根膜細胞の複製能・分化能に影響を及ぼすことが示唆されたことより、高齢者の歯周病の予防、再生治療の有効な治療標的となる可能性が示唆された。

Research Products

• [Presentation] MiR-34a Regutates Stem Cell Aging in Periodontal ligament Stem Cells. (2019)
  • Author(s): Kuniko Ikegami, Motozo Yamashita, Mio Suzuki, Kouki Hashimoto, Tomomi Nakamura, Koji Miki, Manabu Yanagita, Masahiro Kitamura and Shinya Murakami.
  • Organizer: 13th Asian Pacific Society of Periodontology Meeting
  • Int'l Joint Research
• [Presentation] Analysis of Mitophagy in Senescent HPDL Cell. (2019)
  • Author(s): Motozo Yamashita, Mio Suzuki, Kuniko Ikegami, Tomomi Nakamura, Arisa Nishikawa, Kouki Hashimoto, Tatsuya Morikawa, Koji Miki, Manabu Yanagita, Masahiro Kitamura and 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: 2019年度日本歯科保存学会春季学術大会（第150回）
• [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 (2019)
  • Author(s): 辰己真理，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: 2019年度日本歯科保存学会春季学術大会（第150回）
• [Presentation] 老化歯根膜細胞におけるマイトファジーの機能解析 (2019)
  • Author(s): 山下元三、鈴木美麻、池上久仁子、西川有梨沙、橋本康樹、柳田学、北村正博、村上伸也
  • Organizer: 第18回日本再生医療学会総会
• [Presentation] Senescence-associated miR-34a accelerates periodontal stem-cell aging by targeting SATB2 (2018)
  • Author(s): Kuniko Ikegami, Motozo Yamashita, Mio Suzuki, Arisa Nishikawa, Tomomi Nakamura, Koji Miki, Jirouta Kitagaki, Manabu Yanagita, Masahiro Kitamura and Shinya Murakami
  • Organizer: American Academy of Periodontology (AAP) 104th Annual Meeting
  • 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: American Academy of Periodontology (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 and Shinya Murakami
  • Organizer: 第66回国際歯科研究学会日本部会総会・学術大会
  • Int'l Joint Research
• [Presentation] Effects of long-term exposure of cigarette smoke on gingival fibroblasts (2018)
  • Author(s): Mari Tatsumi, Manabu Yanagita, Shiori Hasegawa, Mio Suzuki, Kuniko Ikegami, Motozo Yamashita, Masahiro Kitamura, Shinya Murakami
  • Organizer: 第66回国際歯科研究学会日本部会総会・学術大会
  • Int'l Joint Research
• [Presentation] Dissection of the mitophagy dynamics in HPDL cells by fluorescent probe. (2018)
  • Author(s): Mio Suzuki, Motozo Yamashita, Kuniko Ikegami, Tomomi Nakamura, Arisa Nishikawa, Kouki Hashimoto, Koji Miki, Manabu Yanagita, Masahiro Kitamura, Shinya Murakami
  • Organizer: 第66回国際歯科研究学会日本部会総会・学術大会
  • Int'l Joint Research