Identification of factors promoting final differentiation of cardiac myocytes after birth

• Project/Area Number: 18K06870
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 48020:Physiology-related
• Research Institution: Shinshu University
• Principal Investigator: yamada mitsuhiko 信州大学, 学術研究院医学系, 教授 (10263237)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 新生児 / 心臓 / 細胞分裂 / 分化 / インターロイキン6 / gp130 / 腫瘍心臓病学 / 小児がん / 心筋細胞 / 最終分化因子 / 分裂刺激因子 / 最終分化 / 周産期 / L型Ca2+チャネル / サイトカイン / 増殖因子 / ホルモン

Outline of Final Research Achievements

Different from the widely accepted belief, cardiac myocytes of mammals including human are not ‘terminally differentiated’ at birth. They are still both structurally and functionally too immature to ensure their robust aerobic extrauterine life. In the case of mice, for instance, they cease cell division around 1 week old, and then, start to differentiate to the mature level by approximately one month. Interestingly, we here found for the first time that the most important driver of the initial cell division in the left ventricle is the interleukin 6/gp130 signaling system, and that it is necessary for establishing the normal myocyte number, wall thickness, and the contractility of the left ventricle. Thus, this pathway might be druggable in the regenerative medicine for the late-onset left ventricular dysfunction sometimes manifested in pediatric cancer survivors.

Academic Significance and Societal Importance of the Research Achievements

本研究の学術的意義は，①哺乳類の出生後早期の一過性心筋細胞分裂が，成長後の心臓の形態・機能形成に重要であること，②それが主としてインターロイキン-6／gp130シグナルにより駆動されることを見出したことである。近年，ヒトの心筋細胞も胎児期・新生児期の後も，わずかながら継続的に分裂していることが知られ，再生療法への応用が期待されている。また近年，小児がん治療を受けた小児が，永年後心機能低下生じることがあることが知られ，Oncocardilogy的課題となっている。本研究は，小児心臓病治療にサイトカイン／gp130系が応用できる可能性をはじめて示した社会的意義がある。

Research Products

• [Int'l Joint Research] Technische Universitat Dresden(ドイツ)
• [Journal Article] Increased predominance of the matured ventricular subtype in embryonic stem cell-derived cardiomyocytes in vivo (2020)
  • Author(s): Ichimura Hajime、Kadota Shin、Kashihara Toshihide、Yamada Mitsuhiko、Ito Kuniaki、Kobayashi Hideki、Tanaka Yuki、Shiba Naoko、Chuma Shinichiro、Tohyama Shugo、Seto Tatsuichiro、Okada Kenji、Kuwahara Koichiro、Shiba Yuji
  • Journal Title: Scientific Reports Volume: 10 Issue: 1 Pages: 11883-11883
  • DOI: 10.1038/s41598-020-68373-9
  • NAID: 120007006223
  • Peer Reviewed / Open Access
• [Journal Article] beta-Arrestin-Biased AT1 Agonist, TRV027 Causes a Neonatal-Specific Sustained Positive Inotropic Effect without Increasing Heart Rate (2020)
  • Author(s): Kashihara T, Kawagishi H, Nakada T, Numaga-Tomita T, Kadota S, Wolf EE, Du CK, Shiba Y, Morimoto S, Yamada M.
  • Journal Title: Journal of the American College of Cardiology Volume: 5 Issue: 11 Pages: 1057-1057
  • DOI: 10.1016/j.jacbts.2020.08.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of hypertension and antihypertensive treatments on sulfatide levels in serum and its metabolism (2019)
  • Author(s): Guo Ran、Hu Xiao、Yamada Yosuke、Harada Makoto、Nakajima Takero、Kashihara Toshihide、Yamada Mitsuhiko、Aoyama Toshifumi、Kamijo Yuji
  • Journal Title: Hypertension Research Volume: 42 Issue: 5 Pages: 598-609
  • DOI: 10.1038/s41440-018-0160-z
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Prostanoid EP4 receptor-mediated augmentation of Ih currents in Aβ dorsal root ganglion neurons underlies neuropathic pain (2018)
  • Author(s): Zhang H, Kashihara T, Nakada T, Tanaka S, Ishida K, Fuseya S, Kawagishi H, Kiyosawa K, Kawamata M, Yamada M
  • Journal Title: Journal of Pharmacology and Experimental Therapeutics Volume: 368 Issue: 1 Pages: 50-58
  • DOI: 10.1124/jpet.118.252767
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] PDGF-induced migration of synthetic vascular smooth muscle cells through c-Src-activated L-type Ca2+ channels with full-length CaV1.2 C-terminus (2018)
  • Author(s): Xiaoguang Guo, Toshihide Kashihara, Tsutomu Nakada, Toshifumi Aoyama, Mitsuhiko Yamada
  • Journal Title: Pflugers Archiv - European Journal of Physiology Volume: 470 (6) Issue: 6 Pages: 909-921
  • DOI: 10.1007/s00424-018-2114-3
  • NAID: 130007812887
  • Peer Reviewed
• [Journal Article] Physical interaction of junctophilin and the CaV1.1 C terminus is crucial for skeletal muscle contraction (2018)
  • Author(s): Nakada Tsutomu、Kashihara Toshihide、Komatsu Masatoshi、Kojima Katsuhiko、Takeshita Toshikazu、Yamada Mitsuhiko
  • Journal Title: Proceedings of the National Academy of Sciences Volume: 115 Issue: 17 Pages: 4507-4512
  • DOI: 10.1073/pnas.1716649115
  • Peer Reviewed / Open Access
• [Journal Article] Sonic hedgehog signaling regulates the mammalian cardiac regenerative response (2018)
  • Author(s): Kawagishi Hiroyuki、Xiong Jianhua、Rovira Ilsa I.、Pan Haihui、Yan Ye、Fleischmann Bernd K.、Yamada Mitsuhiko、Finkel Toren
  • Journal Title: Journal of Molecular and Cellular Cardiology Volume: 123 Pages: 180-184
  • DOI: 10.1016/j.yjmcc.2018.09.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Impact of chronic kidney dysfunction on serum Sulfatides and its metabolic pathway in mice (2018)
  • Author(s): Yamada Yosuke、Harada Makoto、Hashimoto Koji、Guo Ran、Nakajima Takero、Kashihara Toshihide、Yamada Mitsuhiko、Aoyama Toshifumi、Kamijo Yuji
  • Journal Title: Glycoconjugate Journal Volume: 36 Issue: 1 Pages: 1-11
  • DOI: 10.1007/s10719-018-9850-7
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Molecular mechanism underlying cardiac early afterdepolarization induced by IKr and IKs suppression (2020)
  • Author(s): Mitsuhiko YAMADA, Toshihide KASHIHRA, Hitoshi NISHIMURA
  • Organizer: The 11th Annual Meeting of Japanese Safety Pharmacology Society
  • Int'l Joint Research / Invited
• [Presentation] Postnatal loss of gp130 caused impaired cardiac contractility accompanied by inhibition of physiological proliferation of cardiomyocytes. (2020)
  • Author(s): Hiroyuki Kawagishi, Tsutomu Nakada, Takuro Numaga-Tomita, Mitsuhiko Yamada
  • Organizer: NIPS International Meeting on Cardiovascular Physiology 2020
  • Int'l Joint Research
• [Presentation] 小胞体CaセンサーSTIM1によるCaV1.2チャネル抑制メカニズムの解明 (2020)
  • Author(s): 冨田拓郎、高橋弘毅、山田充彦
  • Organizer: 第142回日本薬理学会関東部会
• [Presentation] βアレスチンバイアスアンジオテンシン1型受容体アゴニストは、新生児特有の持続性陽性変力作用を示す (2020)
  • Author(s): 川岸裕幸、柏原俊英、冨田拓郎、中田勉、山田充彦
  • Organizer: 第142回日本薬理学会関東部会
• [Presentation] ジャンクトフィリン2変異体の強制発現による心機能低下 (2020)
  • Author(s): 中田勉、川岸裕幸、冨田拓郎、山田充彦
  • Organizer: 第67回中部日本生理学会
• [Presentation] HCN チャネル阻害薬による神経障害性疼痛の治療法 (2020)
  • Author(s): 冨田（沼賀）拓郎、川真田樹人、山田充彦
  • Organizer: 第143回日本薬理学会関東部会
• [Presentation] 新たな方法でAT1 受容体を利用した小児心不全治療薬の開発 (2020)
  • Author(s): 川岸 裕幸、山田 充彦
  • Organizer: 第143回日本薬理学会関東部会
• [Presentation] Ca2+チャネルアゴニストFPL64176の分子作用メカニズム (2020)
  • Author(s): 山田 充彦
  • Organizer: 第143回日本薬理学会関東部会
• [Presentation] 小児心不全では、AT1アンジオテンシン受容体を抑制すべきか刺激すべきか？ (2020)
  • Author(s): 山田充彦
  • Organizer: 第56回日本小児循環器学会総会・学術集会
• [Presentation] アンギオテンシンII 1型受容体-βアレスチン経路を活性化する小児心不全治療薬の開発 (2020)
  • Author(s): 川岸裕幸、柏原俊英、冨田拓郎、中田勉、山田充彦
  • Organizer: 第30回日本循環薬理学会
• [Presentation] 血管平滑筋細胞におけるL型電位依存性カルシウムチャネルとストア作動性カルシウムチャネルの関係性解明 (2020)
  • Author(s): 冨田拓郎、小林誠、川岸裕幸、中田勉、山田充彦
  • Organizer: 第30回日本循環薬理学会
• [Presentation] AT1受容体／βアレスチン経路は小児心不全の治療標的となる (2020)
  • Author(s): 山田充彦
  • Organizer: 第12回日本安全性薬理研究会・学術年会
  • Invited
• [Presentation] A beta arrestin-bias AT1 receptor agonist improves the survival of neonatal knock-in mice bearing a human dilated cardiomyopathy mutation (2019)
  • Author(s): Yamada, M
  • Organizer: The 50th NIPS International Symposium. ‘MIRACLES’ in Cardiovascular Physiology
  • Int'l Joint Research / Invited
• [Presentation] Molecular mechanism underlying cardiac early afterdepolarization induced by IKr and IKs suppression (2019)
  • Author(s): Mitsuhiko YAMADA, Toshihide KASHIHRA, Hitoshi NISHIMURA
  • Organizer: Japanese Safety Pharmacology Society
  • Invited
• [Presentation] Molecular mechanisms underlying spatiotemporal regulation of L-type Ca2+ channels in muscles. (2019)
  • Author(s): Yamada, M.
  • Organizer: ogic of life: ion channel structure, function and physiology. International commemorative symposium in celebration of retirement of Professor Yoshihisa Kurachi
  • Int'l Joint Research / Invited
• [Presentation] Interaction of junctophilins and the CaV1.1 is essential for the skeletal muscle contraction (2019)
  • Author(s): Tsutomu Nakada, Toshihide Kashihara, Masatoshi Komatsu, Mitsuhiko Yamada
  • Organizer: FAOPS 2019
• [Presentation] EP4 receptor-mediated augmentation of Ih currents in A-beta DRG neurons underlies neuropathic pain (2019)
  • Author(s): 31.Yamada, M., Zhang, H., Kashihara, T., Nakada, T., Tanaka, S., Ishida, K., Fuseya, S., Kawagishi, H., Kiyosawa, K., Kawamata, M.
  • Organizer: FAOPS 2019
  • Int'l Joint Research
• [Presentation] PDGF induces migration of synthetic vascular smooth muscle cells through c-Src-dependent activation of full-length CaV1.2 L-type Ca2+ channels (2018)
  • Author(s): Kashihara, T., Guo, X., Nakada, T., Yamada, M.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Presentation] Physical interaction of junctophilins and CaV1.1 subunits is essential for the excitation-contraction coupling of the skeletal muscle. (2018)
  • Author(s): Nakada, T., Kashihara, T., Komatsu, M., Yamada, M.
  • Organizer: 18th World Congress of Basic and Clinical Pharmacology (WCP2018)
  • Int'l Joint Research
• [Book] 熱血 循環器学 （井上信孝 編） (2019)
  • Author(s): 山田充彦
  • Total Pages: 244
  • Publisher: 洋學社
• [Book] 熱血 循環器学 (2019)
  • Author(s): 井上信孝、山田充彦
  • Total Pages: 244
  • Publisher: 洋學社
  • ISBN: 9784908296147
• [Remarks] 信州大学医学部分子薬理学教室ホームページ
  • URL: https://www.shinshu-u.ac.jp/faculty/medicine/chair/i-yakuri/
• [Remarks] 信州大学医学部分子薬理学教室ホームページ
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/chair/i-yakuri/index.html
• [Remarks] 信州大学医学部ホームページ
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/department/medical_science/course/course06.php
• [Remarks] Shinshu University Graduate School of Medicine
  • URL: http://www.shinshu-u.ac.jp/faculty/medicine/eng/graduate/course/36518.html