Maintenance of melanocyte stem cell function by HMGB2 gene expressed in hair follicles.

• Project/Area Number: 19K08746
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Gifu University
• Principal Investigator: Kunisada Takahiro 岐阜大学, 大学院医学系研究科, 教授 (30205108)
• Co-Investigator(Kenkyū-buntansha): 青木 仁美 岐阜大学, 大学院医学系研究科, 講師 (10550361)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
• Keywords: 白髪 / 毛包幹細胞 / HMGB2 / 老化 / 色素細胞幹細胞(MSCs) / 幹細胞ニッシェ / 白髪モデル / 色素細胞幹細胞 / 色素細胞幹細胞ニッシェ因子 / X線

Outline of Research at the Start

X線照射による白毛化（毛包の色素細胞の喪失）の主因が毛包ケラチノサイトのニッシェ機能の喪失であることから、X線照射後のケラチノサイトのプロテオーム解析により発現が変動する遺伝子に注目し、HMGB2遺伝子を同定した。この遺伝子のノックアウトマウスはX線による白毛化の閾値が低いという予備的な結果から、HMGB2が毛包ケラチノサイトに発現する新たな色素細胞幹細胞のニッシェ因子と予想された。本申請では、HMGB2ノックアウトマウスに異なる３種の手法で白毛化を誘導してX線による白毛化を厳密に検証し、白髪との関連及び小分子量化合物などを用いたHMGB2経路の操作による白髪の予防・回復を目指す。

Outline of Final Research Achievements

HMGB2 siRNA was administered to normal human epidermal keratinocytes to reduce the expression level, then X-ray irradiation increased the amount of active oxygen, mitochondrial damage, and DNA damage. Next, HMGB2KO mice prepared by using the CRISPR-Cas9 system, did not show whitening of hair, but caused DNA damage to hair follicle stem cells, resulting in significant radiation-induced whitening. In addition, the amount of HMGB2 decreased in the human epidermis in an age-dependent manner. It was suggested that HMGB2 in the epidermis decreases with aging and contributes to the prevention of hair graying by X-ray radiation.

Academic Significance and Societal Importance of the Research Achievements

HMGB２がどのような老化現象に関わるか詳細に解明するにはHMGB２の発現細胞、発現部位の確認、HMGB２と既存老化マーカーとの相関性などのデータが必要である。さらに、表皮を含めた様々な細胞でHMGB２発現を促進する化合物をスクリーニングすれば、HMGB２を標的にした有効なアンチエイジング薬（白髪防止剤を含む）を提供できると考えている。最近、適度な運動により神経細胞でのHMGB２発現を高め、老化によって減少する海馬の神経刺激・神経新生を促進できることが報告された。このようにHMGB2は様々な老化現象に関与することが知られてきており、注目すべき抗老化因子と考えられる。

Research Products

• [Int'l Joint Research] Institut Curie, PSL Research University(フランス)
• [Journal Article] Targeted Knockout of β-Catenin in Adult Melanocyte Stem Cells Using a Mouse Line, Dct::CreER T2, Results in Disrupted Stem Cell Renewal and Pigmentation Defects (2021)
  • Author(s): Le Coz M, Aktary Z, Watanabe N, Yajima I, Pouteaux M, Charoenchon N, Motohashi T, Kunisada T, Corvelo A, Larue L.
  • Journal Title: J Invest Dermatol. Volume: 141 Issue: 5 Pages: 1363-1366
  • DOI: 10.1016/j.jid.2020.08.025
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Protective effect of hydroxygenkwanin against hair graying induced by X-ray irradiation and repetitive plucking (2021)
  • Author(s): Nobuhiko Taguchi, Ryosuke Kitai, Takuya Ando, Toshihiro Nishimura, Hitomi Aoki, Takahiro Kunisada
  • Journal Title: JID Innovations Volume: 1 Issue: 4 Pages: 1-31
  • DOI: 10.1016/j.xjidi.2022.100121
  • Peer Reviewed / Open Access
• [Journal Article] Dietary <i>Eriodictyon angustifolium</i> Tea Supports Prevention of Hair Graying by Reducing DNA Damage in CD34+ Hair Follicular Keratinocyte Stem Cells (2020)
  • Author(s): Taguchi N, Homma T, Aoki H, Kunisada T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 43 Issue: 10 Pages: 1451-1454
  • DOI: 10.1248/bpb.b20-00455
  • NAID: 130007920879
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2020-10-01
  • Peer Reviewed / Open Access
• [Journal Article] Sox10 Functions as an Inducer of the Direct Conversion of Keratinocytes Into Neural Crest Cells (2020)
  • Author(s): Motohashi Tsutomu、Kawamura Norito、Watanabe Natsuki、Kitagawa Daisuke、Goshima Naoki、Kunisada Takahiro
  • Journal Title: Stem Cells and Development Volume: 29 Issue: 23 Pages: 1510-1519
  • DOI: 10.1089/scd.2020.0106
  • Peer Reviewed / Open Access
• [Journal Article] Eriodictyon angustifolium extract, but not Eriodictyon californicum extract, reduces human hair greying. (2020)
  • Author(s): Taguchi N, Hata T, Kamiya E, Homma T, Kobayashi A, Aoki H, Kunisada T.
  • Journal Title: Int J Cosmet Sci. Volume: 10 Issue: 4 Pages: 1-10
  • DOI: 10.1111/ics.12620
  • Peer Reviewed / Open Access
• [Journal Article] Flavonoids with Two OH Groups in the B-Ring Promote Pigmented Hair Regeneration (2019)
  • Author(s): Taguchi N, Yuriguchi M, Ando T, Kitai R, Aoki H, Kunisada T.
  • Journal Title: Biological and Pharmaceutical Bulletin Volume: 42 Issue: 9 Pages: 1446-1449
  • DOI: 10.1248/bpb.b19-00295
  • NAID: 130007700078
  • ISSN: 0918-6158, 1347-5215
  • Year and Date: 2019-09-01
  • Peer Reviewed / Open Access
• [Journal Article] Characterization of a BAC transgenic mouse expressing Krt19-driven iCre recombinase in its digestive organs (2019)
  • Author(s): Kanayama Tomohiro、Tomita Hiroyuki、Binh Nguyen Huy、Hatano Yuichiro、Aoki Hitomi、Okada Hideshi、Hirata Akihiro、Fujihara Yoshitaka、Kunisada Takahiro、Hara Akira
  • Journal Title: PLOS ONE Volume: 14 Issue: 8 Pages: e0220818-e0220818
  • DOI: 10.1371/journal.pone.0220818
  • Peer Reviewed / Open Access
• [Presentation] 白髪を予防する天然化合物の作用機構 (2021)
  • Author(s): 國貞隆弘，青木仁美，田口暢彦
  • Organizer: 日本色素細胞学会
  • Invited