An integrated approach for cell cycle control of pluripotent stem cell-derived cardiomyocytes

• Project/Area Number: 17H04176
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cardiovascular medicine
• Research Institution: Kyoto University
• Principal Investigator: Yoshida Yoshinori 京都大学, iPS細胞研究所, 准教授 (20447965)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥16,900,000 (Direct Cost: ¥13,000,000、Indirect Cost: ¥3,900,000); Fiscal Year 2020: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000); Fiscal Year 2018: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 細胞周期 / 心筋細胞 / iPS細胞 / 細胞移植 / 循環器 / 再生医療 / 多能性幹細胞 / 再生医学

Outline of Final Research Achievements

In this study, we investigated the cell cycle control of iPS cell-derived cardiomyocytes. We identified that CCA-1 activated the cell cycle of iPS cell-derived cardiomyocytes and increased their proliferative capacity. In addition, we confirmed that the graft efficiency after cell transplantation was improved by transplanting cardiomyocytes treated with CCA-1 into infarcted hearts of immunodeficient mice. Further, comprehensive gene expression analysis identified genes that serve as markers for cell-cycle active cardiomyocytes.

Academic Significance and Societal Importance of the Research Achievements

多能性幹細胞(ES/iPS細胞)から心筋細胞に分化するにつれて細胞周期は不活性化し増殖しない細胞となっていく。またヒト成人の心臓はほとんど分裂しないため一度心筋梗塞などで傷害を受けた心筋は回復しないことが知られている。本研究においてiPS細胞から分化した心筋細胞の細胞周期を制御することを目的として研究を行った。心筋細胞の細胞周期を活性化する化合物を同定し、同化合物を用いて処理した心筋細胞を移植すると移植生着効率が改善することを明らかにした。心筋細胞移植治療においては細胞周期が治療効率に関与すると考えられ、効率の高い細胞移植治療を確立するための重要な知見となることが期待される。

Research Products

• [Journal Article] Targeted Disruption of HLA Genes via CRISPR-Cas9 Generates iPSCs with Enhanced Immune Compatibility (2019)
  • Author(s): Xu Huaigeng、Wang Bo、Ono Miyuki、Kagita Akihiro、Fujii Kaho、Sasakawa Noriko、Ueda Tatsuki、Gee Peter、Nishikawa Misato、Nomura Masaki、Kitaoka Fumiyo、Takahashi Tomoko、Okita Keisuke、Yoshida Yoshinori、Kaneko Shin、Hotta Akitsu
  • Journal Title: Cell Stem Cell Volume: 24 Issue: 4 Pages: 566-578.e7
  • DOI: 10.1016/j.stem.2019.02.005
  • Peer Reviewed / Open Access
• [Journal Article] Towards Precision Medicine With Human iPSCs for Cardiac Channelopathies. (2019)
  • Author(s): Wu JC, Garg P, Yoshida Y, Yamanaka S, Gepstein L, Hulot JS, Knollmann BC, Schwartz PJ.
  • Journal Title: Circ Res. Volume: 125(6) Issue: 6 Pages: 653-658
  • DOI: 10.1161/circresaha.119.315209
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induced Pluripotent Stem Cells and Their Use in Human Models of Disease and Development. (2019)
  • Author(s): Karagiannis P, Takahashi K, Saito M, Yoshida Y, Okita K, Watanabe A, Inoue H, Yamashita JK, Todani M, Nakagawa M, Osawa M, Yashiro Y, Yamanaka S, Osafune K.
  • Journal Title: Physiol Rev Volume: 99 Issue: 1 Pages: 78-114
  • DOI: 10.1152/physrev.00039.2017
  • Peer Reviewed
• [Journal Article] Optical Recording of Action Potentials in Human Induced Pluripotent Stem Cell-Derived Cardiac Single Cells and Monolayers Generated from Long QT Syndrome Type 1 Patients (2019)
  • Author(s): Takaki Tadashi、Inagaki Azusa、Chonabayashi Kazuhisa、Inoue Keiji、Miki Kenji、Ohno Seiko、Makiyama Takeru、Horie Minoru、Yoshida Yoshinori
  • Journal Title: Stem Cells International Volume: 2019 Pages: 1-12
  • DOI: 10.1155/2019/7532657
  • NAID: 120006634620
  • Peer Reviewed / Open Access
• [Journal Article] Induction of Human Induced Pluripotent Stem Cells to Cardiomyocytes Using Embryoid Bodies (2018)
  • Author(s): Hatani T, Miki K, Yoshida Y
  • Journal Title: Methods in Molecular Biology Volume: 1816 Pages: 79-92
  • DOI: 10.1007/978-1-4939-8597-5_6
  • ISBN: 9781493985968, 9781493985975
• [Journal Article] Complex aberrant splicing in the induced pluripotent stem cell?derived cardiomyocytes from a patient with long QT syndrome carrying KCNQ1-A344Aspl mutation (2018)
  • Author(s): Wuriyanghai Yimin、Makiyama Takeru、Sasaki Kenichi、Kamakura Tsukasa、Yamamoto Yuta、Hayano Mamoru、Harita Takeshi、Nishiuchi Suguru、Chen Jiarong、Kohjitani Hirohiko、Hirose Sayako、Yokoi Fumika、Gao Jingshan、Chonabayashi Kazuhisa、Watanabe Ken、Ohno Seiko、Yoshida Yoshinori、Kimura Takeshi、Horie Minoru
  • Journal Title: Heart Rhythm Volume: 15 Issue: 10 Pages: 1566-1574
  • DOI: 10.1016/j.hrthm.2018.05.028
  • Peer Reviewed / Open Access
• [Journal Article] Nano-structural analysis of engrafted human induced pluripotent stem cell-derived cardiomyocytes in mouse hearts using a genetic-probe APEX2. (2018)
  • Author(s): Hatani T, Funakoshi S, Deerinck TJ, Bushong EA, Kimura T, Takeshima H, Ellisman MH, Hoshijima M, Yoshida Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 505(4) Issue: 4 Pages: 1251-1256
  • DOI: 10.1016/j.bbrc.2018.10.020
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Induced Pluripotent Stem Cells Ten Years Later: For Cardiac Applications (2017)
  • Author(s): Yoshida Y, Yamanaka S
  • Journal Title: Circulation Research Volume: 120(12) Issue: 12 Pages: 1958-1968
  • DOI: 10.1161/circresaha.117.311080
  • Peer Reviewed
• [Presentation] Hypoxia in Cell Reprogramming and Differentiationツ? (2020)
  • Author(s): Yoshinori Yoshida
  • Organizer: Keystone symposia
  • Int'l Joint Research / Invited
• [Presentation] Single cell analysis elucidates the mechanism of Cardiac and Hematopoietic differentiation from human pluripotent stem cells (2019)
  • Author(s): Masayuki Umeda, Chihiro Okada, Akira Watanabe, Akifumi Kondo-Takaori, and Yoshinori Yoshida
  • Organizer: ISSCR 17th Annual Meeting
  • Int'l Joint Research
• [Presentation] Generation of Mature Cardiomyocytes from Pluriponte Stem Cells (2019)
  • Author(s): Yoshinori Yoshida
  • Organizer: 40th Heart Rhythm Scientific Sessions
  • Int'l Joint Research / Invited
• [Presentation] Maturation of pluripotent stem cell-derived cardiomyocytes for biomedical applications (2019)
  • Author(s): Yoshinori Yoshida
  • Organizer: ISACB+ISVTE 2019
  • Int'l Joint Research / Invited
• [Presentation] Efficient large-scale purification of human iPSC-derived cardiomyocytes by synthetic microrna switch and magnetic activated cell sorting (2019)
  • Author(s): Takeshi Hatani, Chikako Okubo, Yoshihiko Fujita, Kazuhisa Chonabayashi, Takeshi Kimura, Hirohide Saito, Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Identification of a cell surface marker which is differentially expressed between ventricular and atrial cardiomyocytes derived from human induced-pluripotent stem cell (2019)
  • Author(s): Misato Koakutsu, Kenji Miki, Masako Sasaki, Stephanie Napier, Tomoyuki Nishimoto, Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] The Brand-New Compound Activates Cell Cycle of Induced Pluripotent Stem Cell Derived Cardiomocytes, and Promotes Efficient Cardiac Engraftment (2019)
  • Author(s): Manabu Kasamoto, Shunsuke Funakoshi, Takeshi Hatani, Yoshinori Yoshida, Takeshi Kimura
  • Organizer: American Heart Association Scientific Sessions 2019
  • Int'l Joint Research
• [Presentation] Maturation of pluripotent stem cell-derived cardiomyocytes (2019)
  • Author(s): Yoshinori Yoshida
  • Organizer: 12th Asian-Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Development of hiPSCs-derived 3D heart tissue maturation method using ERRホウ agonist and mechanical stress (2019)
  • Author(s): Yuya Fujiwara, Kohei Deguchi, Masako Sasaki, Yuki Naka, Kenji Miki, Tomoyuki Nishimoto, Yoshinori Yoshida
  • Organizer: CiRA国際シンポジウム2019
  • Int'l Joint Research
• [Presentation] Generation of mature iPSC cardiomyocytes for cardiac regeneration (2019)
  • Author(s): Yoshinori Yoshida
  • Organizer: Joint Workshop in Medicine, University of Zurich and Kyoto University
  • Int'l Joint Research / Invited
• [Presentation] ヒトiPS細胞を用いた肥大型心筋症の病態モデル構築と新規治療法の探索 (2019)
  • Author(s): 吉田善紀
  • Organizer: 第18回再生医療学会
  • Invited
• [Presentation] Efficient Purification of Human iPSC-derived Cardiomyocytes in a Large ScaleUsing a Synthetic MicroRNA Switch and Magnetic-activated Cell Sorting (2019)
  • Author(s): Takeshi Hatani
  • Organizer: 第83回日本循環器学会学術集会
• [Presentation] Generation of human pluripotent stem cell-derived mature cardiomyocytes for biomedical applications (2019)
  • Author(s): Yoshinori Yoshida
  • Organizer: 15th Winter Brain & Heart Symposium 2019
  • Int'l Joint Research / Invited
• [Presentation] iPS細胞を用いた心疾患の新しい治療の開発 (2019)
  • Author(s): 吉田善紀
  • Organizer: シンポジウム「iPS細胞がつくる未来の健康」
  • Invited
• [Presentation] The Discovery of Brand-new Compound which Accelerate the Cell Cycle to Achieve the Efficient iPS cell-derived Cardiomyocyte Engraftment to the Infarction Modeled Mouse (2018)
  • Author(s): Manabu Kasamoto, Takeshi Hatani, Shunsuke Funakoshi, Yoshinori Yoshida, Takeshi Kimura
  • Organizer: 第3回J-ISCP学術集会
• [Presentation] The Discovery of Brand-new Compound which Accelerate the Cell Cycle to Achieve the Efficient iPS cell-derived Cardiomyocyte Engraftment to the Infarction Modeled Mouse. (2018)
  • Author(s): Manabu Kasamoto, Takeshi Hatani, Shunsuke Funakoshi, Chikako Okubo, Tadashi Takak, Kenji Mik, Takeshi Kimura, Yoshinori Yoshida
  • Organizer: ISSCR 16th Annual Meeting
  • Int'l Joint Research
• [Presentation] Toward in vitro construction of iPSC-derived human heart-like tissue (2018)
  • Author(s): Julia Junghof, Koichi Nakayama, Yoshinori Yoshida
  • Organizer: ISSCR 16th Annual Meeting
  • Int'l Joint Research
• [Presentation] Modeling of cardiac diseases using iPS cells (2018)
  • Author(s): Yoshinori Yoshida
  • Organizer: TERMIS2018
  • Int'l Joint Research / Invited
• [Presentation] EFFICIENT CARDIAC REGENERATION THERAPY BY CELL CYCLE ACTIVATION OF IPSC-DERIVED CARDIOMYOCYTES (2018)
  • Author(s): Manabu Kasamoto, Shunsuke Funakoshi, Takeshi Hatani, Takeshi Kimura, Yoshinori Yoshida
  • Organizer: 第2回日本循環器学会基礎研究フォーラム
• [Presentation] Maturation of Pluripotent Stem Cell-Derived Cardiomyocytes (2018)
  • Author(s): Yoshinori Yoshida
  • Organizer: 11th Asian-Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Disease Modeling of Cardiac Diseases Using Induced Pluripotent Stem Cells (2018)
  • Author(s): Yoshinori Yoshida
  • Organizer: 11th Asian-Pacific Heart Rhythm Society Scientific Session
  • Int'l Joint Research / Invited
• [Presentation] Efficient Purification of Human iPSC-derived Cardiomyocytes in a Large ScaleUsing a Synthetic MicroRNA Switch and Magnetic-activated Cell Sorting (2018)
  • Author(s): Takeshi Hatani, Kazuhisa Chonabayashi, Yoshihiko Fujita, Takeshi Kimura, Hirohide Saito, Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] Nano-structural Analysis of Engrafted Human iPSC-derived Cardiomyocytes in a Mouse Model of Myocardial Infarction Using APEX2 (2018)
  • Author(s): Takeshi Hatani, Shunsuke Funakoshi, Thomas J. Deerinck, Eric A. Bushong, Takeshi Kimura, Mark H. Ellisman, Masahiko Hoshijima, Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] EFFICIENT CARDIAC REGENERATION THERAPY BY CELL CYCLE ACTIVATION OF IPSC-DERIVED CARDIOMYOCYTES (2018)
  • Author(s): Manabu Kasamoto, Shunsuke Funakoshi, Takeshi Hatani, Takeshi Kimura, Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2018
  • Int'l Joint Research
• [Presentation] ヒトiPS細胞を用いた肥大型心筋症の病態モデル構築と新規治療法の探索 (2018)
  • Author(s): 吉田善紀
  • Organizer: 第22回日本心不全学会学術集会
  • Invited
• [Presentation] iPS細胞の循環器領域での臨床応用に向けた研究 (2018)
  • Author(s): 吉田善紀
  • Organizer: 小倉ライブデモンストレーション
  • Invited
• [Presentation] Induction of cardiomyocyte maturation for biomedical applications (2018)
  • Author(s): Yoshinori Yoshida
  • Organizer: Technion-Kyoto Joint meeting
  • Int'l Joint Research / Invited
• [Presentation] Generation of mature cardiomyocytes from human pluripotent stem cells (2018)
  • Author(s): Yoshinori Yoshida
  • Organizer: 12th Catholic International Stem Cell Symposium
  • Int'l Joint Research / Invited
• [Presentation] Cardiac regeneration using human iPSC derived cardiomyocytes (2018)
  • Author(s): Yoshinori Yoshida
  • Organizer: Forum of Regenerative Medicine in Taipei
  • Int'l Joint Research / Invited
• [Presentation] Cell Cycle Modification of iPSC-derived ardiomyocyte for Cardiac Cell Therapy. (2018)
  • Author(s): Manabu Kasamoto
  • Organizer: 第82回日本循環器学会学術集会
• [Presentation] Stably Expressed APEX2 Identifies T-tubules and Dyad Formation in Engrafted iPSC-derived Cardiomyocytes in a Mouse Model of Myocardial Infarction. (2017)
  • Author(s): Takeshi Hatani , Shunsuke Funakoshi, Thomas J. Deerinck, Eric A. Bushong, Takeshi Kimura, Shinya Yamanaka, Mark H. Ellisman, Masahiko Hoshijima, Yoshinori Yoshida
  • Organizer: ISSCR 15th Annual Meeting
  • Int'l Joint Research
• [Presentation] Imaging iPSC-derived Cardiomyocytes Engrafted in a Mouse Model of Myocardial Infarction Using Stably Expressed APEX2. (2017)
  • Author(s): Takeshi Hatani, Shunsuke Funakoshi, Thomas J. Deerinck, Eric A. Bushong, Takeshi Kimura, Shinya Yamanaka, Mark H. Ellisman, Masahiko Hoshijima, Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] IPS-Cell-Derived Cardiomyocyte Disease Modeling. (2017)
  • Author(s): Yoshinori Yoshida
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research / Invited
• [Presentation] Elucidation of the mechanism of cardiomyocyte maturation using single cell transcriptome analysis. (2017)
  • Author(s): Yoshinori Yoshida
  • Organizer: ConBio2017
  • Invited
• [Patent(Industrial Property Rights)] 心筋細胞増殖促進剤及びその利用 (2023)
  • Inventor(s): 吉田善紀, 羽渓健, 鈴木涼介, 川端慎吾
  • Industrial Property Rights Holder: 国立大学法人京都大学, 三洋化成工業株式会社
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2023
• [Patent(Industrial Property Rights)] 心筋細胞増殖促進剤及びその利用 (2018)
  • Inventor(s): 吉田善紀/羽溪健/笠本学/舟越俊介
  • Industrial Property Rights Holder: 吉田善紀/羽溪健/笠本学/舟越俊介
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2018-021729
  • Filing Date: 2018