Elucidation of cell fate determination mechanism of skeletal muscle stem cells

• Project/Area Number: 16H03262
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Applied health science
• Research Institution: Osaka University
• Principal Investigator: FUKADA So-ichiro 大阪大学, 薬学研究科, 准教授 (20432445)
• Co-Investigator(Kenkyū-buntansha): 樋野 展正 大阪大学, 薬学研究科, 助教 (90469916)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2018: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2017: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2016: ¥8,320,000 (Direct Cost: ¥6,400,000、Indirect Cost: ¥1,920,000)
• Keywords: 筋サテライト細胞 / カルシトニン受容体 / Notch / Nrf2 / 骨格筋幹細胞 / 静止期 / 未分化 / 筋衛星細胞 / 骨格筋

Outline of Final Research Achievements

We examined three molecules regulating the cell fate decision of muscle satellite cells. We clarified the downstream signaling pathway of calcitonin receptor (in revision). We also demonstrated that Hey1/HeyL forms heterodimers with Hes1, an effector molecule of Notch signaling, which funcions to maintain undifferentiated state of muscle satellite cells (Development 2019). Regarding Nrf2, we showed Nrf2-mediated pathway allow muscle satellite cells to survive without basal lamina-mediated signaling (J. Cell. Physiol., 2019).

Academic Significance and Societal Importance of the Research Achievements

骨格筋幹細胞である、筋サテライト細胞は筋発生・再生に必須の細胞であり、成体においては、休止期・未分化状態で維持されている。我々はこれまでにカルシトニン受容体（CalcR）が休止期の維持に働き、Hey1/L（古典的Notchシグナルのエフェクター分子）が未分化状態の維持に必須であることを明らかにしてきた。
本申請課題においては、申請者のこれまでの成果をさらに発展させることで、筋サテライト細胞の運命を制御するシグナル経路が見えてきた。これらの成果はiPS細胞などからの筋幹細胞分化系に応用ができ、筋ジストロフィーや筋萎縮疾患などの発症解明、治療法開発にやくにたつ可能性がある。

Research Products

• [Int'l Joint Research] Pasteur Institute(フランス)
• [Int'l Joint Research] Max-Planck Institute(ドイツ)
• [Int'l Joint Research] パスツール研究所(フランス)
• [Int'l Joint Research] University of Louisville(米国)
• [Int'l Joint Research] アルバータ大学(カナダ)
• [Int'l Joint Research] パスツール研究所(フランス)
• [Journal Article] Reduced expression of calcitonin receptor is closely associated with age-related loss of the muscle stem cell pool (2019)
  • Author(s): Ikemoto-Uezumi M, Uezumi A, Zhang L, Hashimoto N, Okamura K, Fukada S
  • Journal Title: J Cachexia Sarcopenia Muscle. Rapid Communication Volume: 印刷中
  • Peer Reviewed
• [Journal Article] Cell-autonomous and redundant roles of Hey1 and HeyL in muscle stem cells: HeyL requires Hes1 to bind diverse DNA sites (2019)
  • Author(s): Noguchi Yu-taro、Nakamura Miki、Hino Nobumasa、Nogami Jumpei、Tsuji Sayaka、Sato Takahiko、Zhang Lidan、Tsujikawa Kazutake、Tanaka Toru、Izawa Kohei、Okada Yoshiaki、Doi Takefumi、Kokubo Hiroki、Harada Akihito、Uezumi Akiyoshi、Gessler Manfred、Ohkawa Yasuyuki、Fukada So-ichiro
  • Journal Title: Development Volume: 146 Issue: 4 Pages: 163618-163618
  • DOI: 10.1242/dev.163618
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Adiponectin promotes muscle regeneration through binding to T-cadherin. (2019)
  • Author(s): Tanaka Y, Kita S, Nishizawa H, Fukuda S, Fujishima Y, Obata Y, Nagao H, Masuda S, Nakamura Y, Shimizu Y, Mineo R, Natsukawa T, Funahashi T, Ranscht B, Fukada SI, Maeda N, Shimomura I.
  • Journal Title: Sci. Rep. Volume: 9 Issue: 1 Pages: 1-12
  • DOI: 10.1038/s41598-018-37115-3
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Implication of basal lamina dependency in survival of Nrf2-null muscle stem cells via an antioxidative-independent mechanism. (2019)
  • Author(s): Takemoto Y, Inaba S, Zhang L, Tsujikawa K, Uezumi A, Fukada SI.
  • Journal Title: J Cell Physiol. Volume: 234 Issue: 2 Pages: 1689-1698
  • DOI: 10.1002/jcp.27040
  • Peer Reviewed
• [Journal Article] Muscle regeneration is disrupted by cancer cachexia without loss of muscle stem cell potential. (2018)
  • Author(s): Inaba S, Hinohara A, Tachibana M, Tsujikawa K, Fukada SI.
  • Journal Title: PLoS One. Volume: 13 Issue: 10 Pages: e0205467-e0205467
  • DOI: 10.1371/journal.pone.0205467
  • Peer Reviewed / Open Access
• [Journal Article] Angiotensin-converting enzyme 2 deficiency accelerates and angiotensin 1-7 restores age-related muscle weakness in mice. (2018)
  • Author(s): Takeshita H, Yamamoto K, Nozato S, Takeda M, Fukada SI, Inagaki T, Tsuchimochi H, Shirai M, Nozato Y, Fujimoto T, Imaizumi Y, Yokoyama S, Nagasawa M, Hamano G, Hongyo K, Kawai T, Hanasaki-Yamamoto H, Takeda S, Takahashi T, Akasaka H, Itoh N, Takami Y, Takeya Y, Sugimoto K, Nakagami H, Rakugi H.
  • Journal Title: J Cachexia Sarcopenia Muscle. Volume: 9 Issue: 5 Pages: 975-986
  • DOI: 10.1002/jcsm.12334
  • Peer Reviewed / Open Access
• [Journal Article] Reciprocal signalling by Notch-Collagen V-CALCR retains muscle stem cells in their niche. (2018)
  • Author(s): Baghdadi MB, Castel D, Machado L, Fukada SI, Birk DE, Relaix F, Tajbakhsh S, Mourikis P.
  • Journal Title: Nature Volume: 557 Issue: 7707 Pages: 714-718
  • DOI: 10.1038/s41586-018-0144-9
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] 筋の発生と再生メカニズムの解明 (2018)
  • Author(s): 野口裕太郎, 深田宗一朗
  • Journal Title: Clinical Calcium Volume: 28 Pages: 329-333
• [Journal Article] A novel long non-coding RNA Myolinc regulates myogenesis through TDP-43 and Filip1. (2018)
  • Author(s): Militello G, Hosen MR, Ponomareva Y, Gellert P, Weirick T, John D, Hindi SM, Mamchaoui K, Mouly V, Doring C, Zhang L, Nakamura M, Kumar A, Fukada SI, Dimmeler S, Uchida S
  • Journal Title: J Mol Cell Biol Volume: 10 Pages: 102-17
  • Peer Reviewed / Open Access
• [Journal Article] The roles of muscle stem cells in muscle injury, atrophy, and hypertrophy. (2018)
  • Author(s): Fukada SI.
  • Journal Title: J Biochem. Volume: 163 Pages: 353-8
  • Peer Reviewed
• [Journal Article] The Ror1 receptor tyrosine kinase plays a critical role in regulating satellite cell proliferation during regeneration of injured muscle. (2017)
  • Author(s): Kamizaki K, Doi R, Hayashi M, Saji T, Kanagawa M, Toda T, Fukada SI, Ho HH, Greenberg ME, Endo M, Minami Y
  • Journal Title: J. Biol. Chem. Volume: 292 Pages: 15939-51
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Vestigial-like 2 contributes to normal muscle fiber type distribution in mice (2017)
  • Author(s): Honda M, Hidaka K, Fukada S, Sugawa R, Shirai M, Ikawa M, Morisaki T
  • Journal Title: Sci. Rep. Volume: 7 Pages: 7168-7168
  • NAID: 120006957431
  • Peer Reviewed / Open Access
• [Journal Article] Gm7325 is MyoD-dependently expressed in activated muscle satellite cells. (2017)
  • Author(s): Takei D, Nishi M, Fukada S, Doi M, Okamura H, Uezumi A, Zhang L, Yoshida M, Miyazato M, Ichimura A, Takeshima H.
  • Journal Title: Biomed Res. Volume: 38 Pages: 215-19
  • NAID: 130006865614
  • Peer Reviewed
• [Journal Article] Notch ligands regulate the muscle stem-like state ex vivo but are not sufficient for retaining regenerative capacity (2017)
  • Author(s): Sakai H, Fukuda S, Nakamura M, Uezumi A, Noguchi Y, Sato T, Morita M, Yamada H, Tsuchida K, Tajbakhsh S, Fukada S
  • Journal Title: PLoS One Volume: 12
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] 筋衛星細胞の維持機構及び加齢性筋萎縮への関与 (2017)
  • Author(s): 竹本裕政, 深田宗一朗
  • Journal Title: Clinical Calcium Volume: 27 Pages: 339-344
• [Journal Article] Current translational research and murine models for Duchenne muscular dystrophy (2016)
  • Author(s): Rodrigues M, Echigoya Y, Fukada S, and Yokota T
  • Journal Title: Journal of Neuromuscular Disease Volume: 3 Pages: 29-48
  • Peer Reviewed / Int'l Joint Research
• [Presentation] 骨格筋幹細胞の制御機構 (2019)
  • Author(s): 深田宗一朗
  • Organizer: 第１８回日本再生医療学会総会 シンポジウム34
  • Invited
• [Presentation] Expression and functional analyses of Dlk1 in muscle stem cells and mesenchymal progenitors during muscle regeneration (2019)
  • Author(s): So-ichiro Fukada
  • Organizer: 6th Myology 2019
  • Int'l Joint Research / Invited
• [Presentation] Notchとカルシトニン受容体による筋幹細胞維持メカニズム (2018)
  • Author(s): 深田宗一朗
  • Organizer: 第４１回日本分子生物学会 ワークショップ3AW-11
  • Invited
• [Presentation] 骨格筋幹細胞維持の基盤メカニズム (2018)
  • Author(s): 深田宗一朗
  • Organizer: 第６０回歯科基礎医学会学術大会 シンポジウム
  • Invited
• [Presentation] 筋肥大時における骨格筋幹細胞の増殖メカニズム (2018)
  • Author(s): 深田宗一朗
  • Organizer: 第４回日本筋学会学術集会
  • Invited
• [Presentation] Calcitonin receptor signaling maintains muscle stem cells in quiescent state through PKA-dependent Hippo pathway regulation (2018)
  • Author(s): So-ichiro Fukada, Lidan Zhang, Yu-taro Noguchi
  • Organizer: Muscle 2018
  • Int'l Joint Research
• [Presentation] Molecular mechanism underlying proliferation of muscle stem cells during muscle hypertrophy (2018)
  • Author(s): So-ichiro Fukada, Sumiaki Fukada
  • Organizer: FASEB Science Research Conferences
  • Int'l Joint Research
• [Presentation] 骨格筋幹細胞の静止期と活性化 (2018)
  • Author(s): 深田宗一朗
  • Organizer: 第１７回日本再生医療学会総会 シンポジウム
  • Invited
• [Presentation] 筋幹細胞維持メカニズム研究と筋肥大 (2017)
  • Author(s): 深田宗一朗
  • Organizer: 九州大学医学部 第９回筋生理研究会
  • Invited
• [Presentation] 骨格筋幹細胞の維持メカニズムと筋肥大 (2017)
  • Author(s): 深田宗一朗
  • Organizer: 神戸大学医学部 シグナル伝達医学研究展開センター主催セミナー
  • Invited
• [Presentation] 筋幹細胞は筋線維の質・量維持に貢献できるのか？ (2016)
  • Author(s): 深田宗一朗
  • Organizer: 第６２回日本宇宙航空環境医学会大会・日本宇宙生物科学会第30回大会 合同ワークショップ３
  • Place of Presentation: 愛知医科大学
  • Invited
• [Presentation] 骨格筋幹細胞と筋の恒常性維持 (2016)
  • Author(s): 深田宗一朗
  • Organizer: 東京大学 医科学研究所, 学友会セミナー
  • Place of Presentation: 東京大学 医科学研究所
  • Invited
• [Presentation] 骨格筋の量・質と幹細胞 (2016)
  • Author(s): 深田宗一朗
  • Organizer: 第３４回日本骨代謝学会学術集会 あり方委員会シンポジウム5 筋・腱・靭帯シンポジウム
  • Place of Presentation: 大阪国際会議場
  • Invited
• [Presentation] 骨格筋幹細胞の維持メカニズムとその応用 (2016)
  • Author(s): 深田宗一朗
  • Organizer: 第９回Symphony
  • Place of Presentation: 飯田橋メトロポリタンホテル
  • Invited
• [Presentation] The undifferentiated state of muscle stem cells by Notch effector genes (2016)
  • Author(s): So-ichiro Fukada, Miki Nakamura, Masanobu Hino, Yu-taro Noguchi
  • Organizer: FASEB Science Research Conferences
  • Place of Presentation: Colorado, USA,
  • Int'l Joint Research / Invited
• [Presentation] Molecular regulation of muscle stem cell quiescence, undifferentiation, and survival (2016)
  • Author(s): So-ichiro Fukada
  • Organizer: University of Minnesota Medical School, Symposium, “Cardiac and Skeletal Muscle Stem Cell and Regeneration”
  • Place of Presentation: University of Minnesota Medical School
  • Int'l Joint Research / Invited
• [Remarks] HP
  • URL: https://fukada88.wixsite.com/mysite