Elucidation of the mechanisms for hair follicle aging focusing on stem cell divisions

• Project/Area Number: 18H02637
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Matsumura Hiroyuki 東京医科歯科大学, 難治疾患研究所, 助教 (70581700)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2019: ¥5,590,000 (Direct Cost: ¥4,300,000、Indirect Cost: ¥1,290,000); Fiscal Year 2018: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 毛包幹細胞 / 幹細胞分裂 / １７型コラーゲン / aPKCλ / 老化 / 細胞極性 / ヘミデスモソーム

Outline of Final Research Achievements

Hair follicles, mammalian mini-organs that grow hair, miniaturize during aging, leading to hair thinning and loss. In this study, we revealed that hair follicle stem cells (HFSCs) lose their regenerative capabilities during aging owing to the adoption of an atypical cell division program. This type of division is accompanied by the destabilization of hemidesmosomal protein COL17A1 and cell polarity protein aPKCλ and generates terminally differentiating epidermal cells instead of regenerating the hair follicle niche. With the repetition of these atypical divisions, HFSCs detach from the basal membrane causing their exhaustion, elimination and organ aging. These results demonstrate that distinct stem cell division programs may govern tissue and organ aging.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、哺乳類の上皮系器官において再生と老化を担う幹細胞分裂プログラムの存在がはじめて明らかにした。これにより、加齢によって質の低下した幹細胞を効率よく生体から排除し、毛包自体も小型化し機能低下に至ることを世界に先駆けて解明した。また本成果は、器官の再生と老化の機序において幹細胞分裂がいかに中心的な役割を果たしうるかを明確に示すと同時に、加齢に伴う脱毛症の新規治療法開発やその他の上皮系臓器の加齢関連疾患の機構解明やその治療法開発にも繋がるものと期待される。

Research Products

• [Journal Article] Dynamic stem cell selection safeguards the genomic integrity of the epidermis (2021)
  • Author(s): Kato Tomoki、Liu Nan、Morinaga Hironobu、Asakawa Kyosuke、Muraguchi Taichi、Muroyama Yuko、Shimokawa Mariko、Matsumura Hiroyuki、Nishimori Yuriko、Tan Li Jing、Hayano Motoshi、Sinclair David A.、Mohri Yasuaki、Nishimura Emi K.
  • Journal Title: Developmental Cell Volume: 56 Issue: 24 Pages: 3309-3320
  • DOI: 10.1016/j.devcel.2021.11.018
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] EGFR-mediated epidermal stem cell motility drives skin regeneration through COL17A1 proteolysis (2021)
  • Author(s): Nanba D, Toki F, Asakawa K, Matsumura H, Shiraishi K, Sayama K, Matsuzaki K, Toki H, Nishumura EK.
  • Journal Title: J Cell Biol Volume: 220 Issue: 11
  • DOI: 10.1083/jcb.202012073
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Obesity accelerates hair thinning by stem cell-centric converging mechanisms (2021)
  • Author(s): Morinaga H, Mohri Y, Grachtchouk M, Asakawa K, Matsumura H, Oshima M, Takayama N, Kato T, Nishimori Y, Sorimachi Y,?Takubo K, Suganami T, Iwama A, Iwakura Y, Dlugosz AA, Nishimura EK.
  • Journal Title: Nature Volume: 595 Issue: 7866 Pages: 266-271
  • DOI: 10.1038/s41586-021-03624-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles (2021)
  • Author(s): Matsumura H, Liu N, Nanba D, Ichinose S, Takada A, Kurata S, Morinaga H, Mohri Y, Adele De Arcangelis, Ohno S, Nishimura E K
  • Journal Title: Nature Aging Volume: 1 Pages: 190-204
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] NUAK2 localization in normal skin and its expression in a variety of skin tumors with YAP (2020)
  • Author(s): Al-Busani Hind、Al-Sobaihi Saber、Nojima Kohei、Tanemura Atsushi、Yaguchi Tomonori、Kawakami Yutaka、Matsumura Hiroyuki、Nishimura Emi K.、Yokozeki Hiroo、Namiki Takeshi
  • Journal Title: Journal of Dermatological Science Volume: 97 Issue: 2 Pages: 143-151
  • DOI: 10.1016/j.jdermsci.2020.01.008
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Stem cell competition orchestrates skin homeostasis and ageing (2019)
  • Author(s): Liu N, Matsumura H, Kato T, Ichinose S, Takada A, Namiki T, Asakawa K, Morinaga H, Mohri Y, De Arcangelis A, Geroges-Labouesse E, Nanba D, Nishimura EK
  • Journal Title: Nature Volume: 568(7752) Issue: 7752 Pages: 344-350
  • DOI: 10.1038/s41586-019-1085-7
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Beclin 1 regulates recycling endosome and is required for skin development in mice (2019)
  • Author(s): Noguchi Saori、Honda Shinya、Saitoh Tatsuya、Matsumura Hiroyuki、Nishimura Emi、Akira Shizuo、Shimizu Shigeomi
  • Journal Title: Communications Biology Volume: 2 Issue: 1 Pages: 37-37
  • DOI: 10.1038/s42003-018-0279-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles (2021)
  • Author(s): 松村 寛行○
  • Organizer: 第44回日本分子生物学会年会・ワークショップ
  • Invited
• [Presentation] 幹細胞分裂タイプの違いが毛包の再生と老化の運命を決定する (2021)
  • Author(s): 松村 寛行○
  • Organizer: 第８回皮膚の会
• [Presentation] Distinct stem cell division programs determine organ regeneration and aging in hair follicles (2020)
  • Author(s): Hiroyuki Matsumura○, Nan Liu, Daisuke Nanba, Shizuko Ichinose, Aki Takada, Sotaro Kurata, Hironobu Morinaga, Yasuaki Mohri, Adle De Arcangelis, Shigeo Ohno, Emi K. Nishimura
  • Organizer: ESDR(European Society for Dermatological Research) 2021
  • Int'l Joint Research
• [Presentation] Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles (2020)
  • Author(s): Hiroyuki Matsumura○, Nan Liu, Daisuke Nanba, Shizuko Ichinose, Aki Takada, Sotaro Kurata, Hironobu Morinaga, Yasuaki Mohri, Adle De Arcangelis, Shigeo Ohno, Emi K. Nishimura
  • Organizer: ISSCR (International Society for Stem Cell Research) 2021 Virtual
  • Int'l Joint Research
• [Presentation] Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles (2020)
  • Author(s): Hiroyuki Matsumura○, Nan Liu, Daisuke Nanba, Shizuko Ichinose, Aki Takada, Sotaro Kurata, Hironobu Morinaga, Yasuaki Mohri, Adle De Arcangelis, Shigeo Ohno, Emi K. Nishimura
  • Organizer: 18th Stem Cell Research Symposium
  • Int'l Joint Research
• [Presentation] Distinct types of stem cell divisions determine organ regeneration and aging in hair follicles (2020)
  • Author(s): 松村 寛行○
  • Organizer: 2021年度東京医科歯科大学難治疾患研究所研究発表会, 最優秀論文賞発表
  • Invited
• [Presentation] 幹細胞競合が皮膚の恒常性維持と老化を司る: (2019)
  • Author(s): 松村 寛行○
  • Organizer: 第42回日本分子生物学会年会・ワークショップ
  • Invited
• [Presentation] 幹細胞ダイナミクスを中心とした皮膚老化機構の解明 (2019)
  • Author(s): 松村 寛行○
  • Organizer: 昭和大学学士会後援会セミナー
  • Invited
• [Presentation] Epidermal stem cell competition orchestrates skin homeostasis and ageing. (2019)
  • Author(s): Hiroyuki Matsumura○, Nan Liu, Tomoki Kato, Shizuko Ichinose, Aki Takada, Takeshi Namiki, Kyosuke Asakawa, Hironobu Morinaga, Yasuaki Mohri, Daisuke Nanba, Emi K. Nishimura:
  • Organizer: ESDR 2019
  • Int'l Joint Research
• [Presentation] Stem cell competition and division govern skin homeostasis and ageing. (2019)
  • Author(s): Hiroyuki Matsumura○, Nan Liu, Tomoki Kato, Shizuko Ichinose, Aki Takada, Takeshi Namiki, Kyosuke Asakawa, Hironobu Morinaga, Yasuaki Mohri, Daisuke Nanba, Emi K. Nishimura:
  • Organizer: ISSCR 2019
  • Int'l Joint Research
• [Presentation] 上皮系臓器の老化の仕組み：幹細胞競合が司る皮膚の恒常性と老化について (2019)
  • Author(s): 松村 寛行○、劉 楠、西村栄美
  • Organizer: 第１９回抗加齢医学会総会
  • Invited
• [Presentation] Stem cell competition and division govern skin homeostasis and ageing. (2019)
  • Author(s): Nan Liu, Hiroyuki Matsumura○, Tomoki Kato, Shizuko Ichinose, Aki Takada, Takeshi Namiki, Kyosuke Asakawa, Hironobu Morinaga, Yasuaki Mohri, Daisuke Nanba, Emi K. Nishimura
  • Organizer: International skin conference Japan-Singapore.
  • Int'l Joint Research
• [Presentation] Epidermal stem cell competition coupled with stem cell divisions in mammalian epidermis (2019)
  • Author(s): Nan Liu, Hiroyuki Matsumura○, Tomoki Kato, Daisuke Nanba, Emi K. Nishimura
  • Organizer: Keystone Symposia 2019, Cell Competition in Development and Disease
  • Int'l Joint Research
• [Book] 細胞個性に基づく幹細胞競合と皮膚再生・老化 (2021)
  • Author(s): 松村 寛行、西村 栄美
  • Total Pages: 5
  • Publisher: 月刊細胞、2021年9月号
• [Book] 幹細胞分裂タイプの違いが毛包の老化と再生を決定する (2021)
  • Author(s): 松村 寛行、西村 栄美
  • Total Pages: 5
  • Publisher: 実験医学, 39(11),1757-1761(2021)
• [Book] 表皮幹細胞の細胞競合と皮膚の再生・老化 (2020)
  • Author(s): 松村 寛行、劉 楠、西村 栄美
  • Total Pages: 8
  • Publisher: 医学のあゆみ,274(5), 491-499,(2020) 細胞競合による生体制御とがん
• [Book] 幹細胞競合が皮膚の恒常性維持と老化を担う (2020)
  • Author(s): 松村 寛行、劉 楠、西村 栄美
  • Total Pages: 2
  • Publisher: 医学のあゆみ,274(7),597-598,(2020)
• [Book] 細胞競合が担う皮膚の恒常性維持と老化 (2020)
  • Author(s): 松村 寛行、劉 楠、西村 栄美
  • Total Pages: 6
  • Publisher: 臨床皮膚科,74(5),37-43,(2020)「最近のトピックス２０２０」
• [Book] 医学のあゆみ、幹細胞競合が皮膚の恒常性維持と老化を担う (2020)
  • Author(s): 松村 寛行、劉 楠、西村 栄美
  • Total Pages: 2
  • Publisher: 医歯薬出版
• [Book] 臨床皮膚科、細胞競合が担う皮膚の恒常性維持と老化 (2020)
  • Author(s): 松村 寛行、劉 楠、西村 栄美
  • Total Pages: 7
  • Publisher: 医学書院
• [Book] 再生医療、表皮幹細胞の細胞競合が担う皮膚の再生・老化 (2019)
  • Author(s): 劉 楠、松村 寛行、西村 栄美
  • Total Pages: 16
  • Publisher: メディカルレビュー社