Function and regulation of Nrf2 in mesenchymal stem cells

• Project/Area Number: 16K01484
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Rehabilitation science/Welfare engineering
• Research Institution: Kindai University
• Principal Investigator: FUKUDA Kanji 近畿大学, 医学部, 教授 (50201744)
• Co-Investigator(Kenkyū-buntansha): 小野寺 勇太 近畿大学, 医学部附属病院, 助手 (30510911) ; 寺村 岳士 近畿大学, 医学部附属病院, 講師 (40460901) ; 丹羽 淳子 近畿大学, 医学部, 講師 (60122082) ; 高橋 英夫 近畿大学, 医学部, 教授 (60335627) ; 竹原 俊幸 近畿大学, 医学部, 助教 (60580561)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 間葉系幹細胞 / 幹細胞老化 / ロコモティブシンドローム / miRNA / 酸化ストレス / Nrf2 / サルコペニア / ロコモ

Outline of Final Research Achievements

Accumulation of reactive oxygen species (ROS) is a major indication of aging and could be a direct reason for tissue degeneration. Nrf2 is a master transcription factor for the anti-oxidation-related genes and disturbing its expression level lead to attenuation of the redox systems. We found that expression of Nrf2 is suppressed in aged bone marrow tissues and muscles. We found here that aging-associated-inflammation commonly observed in various aged tissues and disruption of Notch1 expression trigger overexpression of miR-155, and miR-155 inhibits expression of Nrf2 through suppression of C/ebpβ. This mechanism is conserved in bone marrow mesenchymal stem cells (MSCs) and muscular satellite cells. Results of transcriptome analysis on Nrf2 KO mice showed that Nrf2 could participate various stem cell function such as self-renewal and maintenance of epigenetic status, thus regulation of Nrf2 could be an attractive target molecule for anti-aging therapy of various locomotive tissues.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、加齢に伴う運動組織の退行メカニズムの解明に寄与する。また、本研究では運動負荷、ヒアルロン酸投与の二法により、抗酸化ストレスあるいは幹細胞機能の維持に重要な転写因子Nrf2の発現を賦活できる可能性を報告している。研究成果をさらに発展させることで、近年社会的な問題になっているロコモティブシンドロームをはじめとした、加齢性運動機能障害の新規治療法の開発に貢献しうると考えられる。

Research Products

• [Journal Article] Inflammation-associated miR-155 activates differentiation of muscular satellite cells (2018)
  • Author(s): Onodera Yuta、Teramura Takeshi、Takehara Toshiyuki、Itokazu Maki、Mori Tatsufumi、Fukuda Kanji
  • Journal Title: PLOS ONE Volume: 13 Issue: 10 Pages: 204860-204881
  • DOI: 10.1371/journal.pone.0204860
  • Peer Reviewed / Open Access
• [Journal Article] Stem cell depletion by inflammation-associated miR-155 (2018)
  • Author(s): Teramura Takeshi、Onodera Yuta
  • Journal Title: Aging Volume: 10 Issue: 1 Pages: 17-18
  • DOI: 10.18632/aging.101374
  • Peer Reviewed / Open Access
• [Journal Article] miR-155 induces ROS generation through downregulation of antioxidation-related genes in mesenchymal stem cells (2017)
  • Author(s): Onodera Yuta、Teramura Takeshi、Takehara Toshiyuki、Obora Kayoko、Mori Tatsufumi、Fukuda Kanji
  • Journal Title: Aging Cell Volume: 16 Issue: 6 Pages: 1369-1380
  • DOI: 10.1111/acel.12680
  • Peer Reviewed
• [Journal Article] Hyaluronic Acid Accelerates Tendon-to-Bone Healing After Rotator Cuff Repair. (2017)
  • Author(s): Honda H, Gotoh M, Kanazawa T , Ohzono H, Nakamura H, Ohta K, Nakamura K, Fukuda K, Teramura T, Hashimoto T, Shichijo S, Shiba N
  • Journal Title: The American Journal of Sports Medicine Volume: 45(14) Issue: 14 Pages: 3322-3330
  • DOI: 10.1177/0363546517720199
  • Peer Reviewed / Open Access
• [Journal Article] Inflammation-induced miRNA-155 inhibits self-renewal of neural stem cells via suppression of CCAAT/enhancer binding protein β (C/EBPβ) expression (2017)
  • Author(s): Obora K, Onodera Y, Takehara T, Frampton J, Hasei J, Ozaki T, Teramura T, Fukuda K
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 43604-43604
  • DOI: 10.1038/srep43604
  • Peer Reviewed / Open Access