The role of microRNA146b-5p for scar-less healing in skin wounds

• Project/Area Number: 19K10017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56070:Plastic and reconstructive surgery-related
• Research Institution: Toho University
• Principal Investigator: Akasaka Yoshikiyo 東邦大学, 医学部, 教授 (60202511)
• Co-Investigator(Kenkyū-buntansha): 藤澤 千恵 東邦大学, 医学部, 講師 (10393000) ; 大西 清 東邦大学, 医学部, 名誉教授 (30194228) ; 中道 美保 東邦大学, 医学部, 助教 (70804178)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 皮膚 / 瘢痕 / microRNA / 線維芽細胞 / bFGF / PDGFα / 脂肪組織 / 創傷治癒 / PDGFRα / Exosome / 筋線維芽細胞 / 間葉系幹細胞

Outline of Research at the Start

最近申請者らがbFGF投与線維芽細胞のマイクロアレイ解析で探索したmiRNA146bは、標的Platelet derived growth factor receptor α(PDGFRα)の発現抑制からCollagen産生を低下させ培養細胞レベルで線維化抑制能を示す。今回miRNA146bの瘢痕抑制能を生体内で実証するため、miRNA146bノックアウトラットでmiRNA146b欠失による瘢痕形成促進能の証明とPDGFRα陽性の間葉性幹細胞の増殖促進能を検討する。最終的にmiRNA146bによる瘢痕抑制能をin vivoで実証し、その包括的な制御におけるmiR146bの関与を解明する。

Outline of Final Research Achievements

We found miRNA146b-5p preferentially upregulated in wound fibroblasts by bFGF and identified PDGFRα as a direct target of miRNA146b-5p. miRNA146b-5p led to markedly repressed fibrosis in skin wounds, with decreased expression of PDGFRα in wounds. These results indicate the positive effects of miRNA146b-5p for the suppression of fibrosis, possibly through the inhibition of PDGFRα. Notably, we discovered the specific colocalization of the exosome marker CD81 and miRNA146b-5p in the fibroblastic cells of adipose tissues following mimic transfection. Therefore, fibroblastic cells of adipose tissues, which may specifically pick up and contain miRNA146b-5p via exosome, may play an important role in the suppression of dermal fibrosis. In this process, miRNA146b-5p may inhibit PDGFRα expression in fibro-adipogenic progenitors, which will lead to the inhibition of wound fibrosis via the repression of PDGFRα-induced profibrotic activities along with myofibroblast transition.

Academic Significance and Societal Importance of the Research Achievements

我々はラットの実験系を用いて皮膚傷痕の瘢痕を小さくするmicroRNA146b-5pを世界で初めて明らかにしました。皮膚の傷口は目立たない瘢痕になりますが、ケロイドや肥厚性瘢痕では逆に瘢痕が大きくなります。本研究ではmicroRNA146b-5pによりラット皮膚傷痕の瘢痕が小さくなる新知見を明らかにしました。本研究の成果は、microRNA146b-5pが皮膚の傷痕における瘢痕線維化の抑制メカニズムを解明するのみならず、microRNA146b-5pを直接投与することで傷害臓器で生じる線維化を抑制して線維化臓器における機能不全の予防につながることが期待されます。

Research Products

• [Journal Article] The Role of Mesenchymal Stromal Cells in Tissue Repair and Fibrosis. (2022)
  • Author(s): Akasaka Y
  • Journal Title: Adv Wound Care Volume: - Issue: 11 Pages: 561-574
  • DOI: 10.1089/wound.2021.0037
  • Peer Reviewed
• [Journal Article] Early clinical signs and treatment of Menkes disease. (2022)
  • Author(s): Fujisawa C, Kodama H, Sato Y, Mimaki M, Yagi M, Awano H, Matsuo M, Shintaku H, Yoshida S, Takayanagi M, Kubota M, Takahashi A, Akasaka Y.
  • Journal Title: Mol Genet Metab Rep. Volume: 31 Pages: 100849-100849
  • DOI: 10.1016/j.ymgmr.2022.100849
  • Peer Reviewed / Open Access
• [Journal Article] The Role for miR-146b-5p in the Attenuation of Dermal Fibrosis and Angiogenesis by Targeting PDGFRα in Skin Wounds. (2021)
  • Author(s): Fujisawa C, Hamanoue M, Kawano Y, Murata D, Akishima-Fukasawa Y, Okaneya T, Minematsu T, Sanada H, Tsuburaya K, Isshiki T, Mikami T, Hanawa T, Akasaka Y.
  • Journal Title: J Invest Dermatol. Volume: - Issue: 7 Pages: 1-10
  • DOI: 10.1016/j.jid.2021.11.037
  • Peer Reviewed / Open Access
• [Journal Article] Angiogenesis in mammary Paget disease: histopathol ogical analyses of blood vessel density and angiogenic factors. (2020)
  • Author(s): Akishima-Fukasawa Y, Honma N, Ogata H, Akasaka Y, Mikami T
  • Journal Title: Diagnostic pathology Volume: 15 Issue: 1 Pages: 75-75
  • DOI: 10.1186/s13000-020-00988-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] A Study of Morphological Changes in Renal Afferent Arterioles induced by Angiotensin II Type 1 Receptor Blockers in Hypertensive Patients (2020)
  • Author(s): Nagai Y, Yamabe F, Sasaki Y, Ishii T, Nakanishi K, Nakajima K, Shibuya K, Mikami T, Akasaka Y, Urita Y, Yamanaka N.
  • Journal Title: Kidney Blood Press Res Volume: 45 Issue: 2 Pages: 194-208
  • DOI: 10.1159/000505025
  • Peer Reviewed
• [Journal Article] Activation of mucosal-associated invariant T cells in the lungs of sarcoidosis patients. (2019)
  • Author(s): Matsuyama H, Isshiki T, Chiba A, Yamaguchi T, Murayama G, Akasaka Y, Eishi Y, Sakamoto S, Homma S, Miyake S.
  • Journal Title: Scientific Reports Volume: 9 Issue: 1 Pages: 13181-13181
  • DOI: 10.1038/s41598-019-49903-6
  • Peer Reviewed / Open Access
• [Journal Article] Folylpolyglutamate synthase is a major determinant of intracellular methotrexate polyglutamates in patients with rheumatoid arthritis. (2016)
  • Author(s): Yamamoto T, Shikano K, Nanki T, Kawai S.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 149-150
  • DOI: 10.1038/srep35615
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] microRNAによる瘢痕抑制機構の解明と新展開 (2021)
  • Author(s): 赤坂喜清
  • Organizer: 第51回日本創傷治癒学会
  • Invited
• [Presentation] Induction of angiogenic fibrocytes by basic fibroblast growth factor in vitro. (2020)
  • Author(s): Yoshikiyo Akasaka, Chie Fujisawa, Tetsuya Okaneya, Miho Nakamichi, Kiyoshi Onishi, Yuri Akishima-Fukasawa, Sachie Kanada, Na oko Honma, Tetuo Mikami
  • Organizer: 2020 WHS Annual Me eting, San Diego, California
  • Int'l Joint Research
• [Presentation] 増殖因子受容体を標的にするmicroRNA146bによ る瘢痕線維化の制御機構. (2020)
  • Author(s): 赤坂喜清, 藤澤千恵, 岡根谷哲也, 金田幸枝, 深澤由里, 本間尚子, 三上哲夫
  • Organizer: 第109回日本病理学会総会, WEB, 2020/07
• [Presentation] 高齢者triple-negative乳癌の臨床病理学的 特徴 (2020)
  • Author(s): 本間尚子, 新井冨生, 深澤由里, 金田幸枝, 藤澤千恵, 赤坂喜清, 澁谷和俊, 三上哲夫
  • Organizer: 第109回日本病理学会総会, WEB, 2020/07
• [Presentation] bFGF による骨髄間葉系前駆細胞(Fibrocyte) の誘導とケモカインの発現増加 (2020)
  • Author(s): 岡根谷哲哉、藤澤 千恵、青木 茂久、 荻野 晶弘、岡田 恵美、三上 哲夫、 林 明照、赤坂 喜清
  • Organizer: 第50回日本病理学会総会, WEB, 2020/11
• [Presentation] 増殖因子受容体を標的化する microRNA の探索と瘢痕制御機能の解析 (2020)
  • Author(s): 赤坂 喜清、藤澤 千恵、岡根谷哲哉 、深澤 由里 、本間 尚子、三上 哲夫、 河野 弥生、村田 大貴、花輪 剛久
  • Organizer: 第50回日本病理学会総会, WEB, 2020/11
• [Presentation] In vitro evidence of angiogenic properties of fibrocytes by bFGF (2019)
  • Author(s): Yoshikiyo Akasaka, Chie Fujisawa, Tetsuya Okaneya, Miho Nakamichi, Kiyoshi Onishi, Yuri Akishima-Fukasawa, Naoko Honma, Tetuo Mikami
  • Organizer: 31th Annual Meeting of Wound Healing Society
  • Int'l Joint Research
• [Presentation] bFGFによる骨髄間葉系前駆細胞(Fibrocyte)の誘導と血管形成の証明 (2019)
  • Author(s): 岡根谷哲哉、中道美保、藤澤千恵、青木茂久、荻野晶弘、岡田恵美、三上哲夫、大西 清、赤坂喜清
  • Organizer: 第28回日本形成外科学会・基礎学術集会
• [Presentation] bFGF誘導性の瘢痕線維化を制御するmicroRNAの探索と機能解析 (2019)
  • Author(s): 藤澤千恵、岡根谷哲哉、中道美保、深澤由里、三上哲夫、赤坂喜清
  • Organizer: 第49回日本創傷治癒学会
• [Presentation] bFGFによるCXCL12-CXCR4シグナル増加と骨髄間葉系前駆細胞(Fibrocyte)の誘導 (2019)
  • Author(s): 岡根谷哲哉、中道美保、藤澤千恵、青木茂久、荻野晶弘、岡田恵美、三上哲夫、大西 清、赤坂喜清
  • Organizer: 第49回日本創傷治癒学会
• [Presentation] 創傷治癒におけるbFGFの機能と役割 (2019)
  • Author(s): 赤坂喜清、藤澤千恵、中道美保、岡根谷哲哉
  • Organizer: 第49回日本創傷治癒学会
  • Invited