Discovery of master regulator of cardiac progenitor cells for PSC differentiation into CMs

• Project/Area Number: 16K19426
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: University of Tsukuba (2018); Keio University (2016-2017)
• Principal Investigator: Sadahiro Taketaro 筑波大学, 附属病院, 病院講師 (60571130)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 心臓再生 / ダイレクトリプログラミング / 線維芽細胞 / 多能性幹細胞 / 心筋再生 / 心臓中胚葉 / 幹細胞 / 心臓前駆細胞 / 再生医学

Outline of Final Research Achievements

Cardiac progenitor cell(CPC) arises from pluripotent stem cells and differentiates into cardiomyocytes. However, the molecular mechanisms underlying this process remain unclear. Here we show Tbx6 induces CPCs from pluripotent stem cells (PSCs) and determines cardiovascular lineage specification via its temporal expression. Direct reprogramming-based screening identified Tbx6 was a CPC-inducing factor. Thus, Tbx6 is critical for CPCinduction and subsequent lineage diversification.

Academic Significance and Societal Importance of the Research Achievements

Tbx6をマウスES細胞・ヒトiPS細胞に導入することにより、液性因子を使用せずに効率よく増殖可能な心臓前駆細胞を作製し、さらにこれを心筋細胞や血管細胞を誘導することに成功し、液性因子を使用しない新たな心筋・血管細胞作製法を開発した。本研究で開発した手法は、その誘導効率が従来の液性因子を使用した誘導法よりも優れていただけでなく、高額な液性因子を使用しないため、心筋誘導法における問題点であったコストを約80%削減でき、再生医療や心筋細胞作製に大きく貢献すると予想される。

Research Products

• [Journal Article] Progress and Challenge of Cardiac Regeneration to Treat Heart Failure (2019)
  • Author(s): Isomi Mari、Sadahiro Taketaro、Ieda Masaki
  • Journal Title: Journal of Cardiology Volume: 73 Issue: 2 Pages: 97-101
  • DOI: 10.1016/j.jjcc.2018.10.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Rapid and high-efficient generation of mutant mice using freeze-thawed embryos of the C57BL/6J strain (2019)
  • Author(s): Darwish Mohamed、Nishizono Hirofumi、Uosaki Hideki、Sawada Hitomi、Sadahiro Taketaro、Ieda Masaki、Takao Keizo
  • Journal Title: Journal of Neuroscience Methods Volume: 317 Pages: 149-156
  • DOI: 10.1016/j.jneumeth.2019.01.010
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Role of cyclooxygenase-2-mediated prostaglandin E2-prostaglandin E receptor 4 signaling in cardiac reprogramming (2019)
  • Author(s): Muraoka Naoto、Nara Kaori、Tamura Fumiya、Kojima Hidenori、Yamakawa Hiroyuki、Sadahiro Taketaro、Miyamoto Kazutaka、Isomi Mari、Haginiwa Sho、Tani Hidenori、Kurotsu Shota、Osakabe Rina、Torii Satoru、Shimizu Shigeomi、Okano Hideyuki、Sugimoto Yukihiko、Fukuda Keiichi、Ieda Masaki
  • Journal Title: Nature Communications Volume: 10 Issue: 1 Pages: 674-674
  • DOI: 10.1038/s41467-019-08626-y
  • NAID: 120007128245
  • Peer Reviewed / Open Access
• [Journal Article] Tbx6 Induces Nascent Mesoderm from Pluripotent Stem Cells and Temporally Controls Cardiac versus Somite Lineage Diversification. (2018)
  • Author(s): Sadahiro T, Isomi M, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tamura F, Tani H, Tohyama S, Fujita J, Miyoshi H, Kawamura Y, Goshima N, Iwasaki YW, Murano K, Saito K, Oda M, Andersen P, Kwon C, Uosaki H, Nishizono H, Fukuda K, Ieda M
  • Journal Title: Cell stem cell Volume: 23(3) Issue: 3 Pages: 382-395
  • DOI: 10.1016/j.stem.2018.07.001
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct Cardiac Reprogramming: A Novel Approach for Heart Regeneration (2018)
  • Author(s): Tani Hidenori、Sadahiro Taketaro、Ieda Masaki
  • Journal Title: International Journal of Molecular Sciences Volume: 19 Issue: 9 Pages: 2629-2629
  • DOI: 10.3390/ijms19092629
  • NAID: 120007128488
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Distinct expression patterns of Flk1 and Flt1 in the coronary vascular system during development and after myocardial infarction (2018)
  • Author(s): Kurotsu Shota、Osakabe Rina、Isomi Mari、Tamura Fumiya、Sadahiro Taketaro、Muraoka Naoto、Kojima Hidenori、Haginiwa Sho、Tani Hidenori、Nara Kaori、Kubota Yoshiaki、Ema Masatsugu、Fukuda Keiichi、Suzuki Takeshi、Ieda Masaki
  • Journal Title: Biochem Biophys Res Commun Volume: 495 Issue: 1 Pages: 884-891
  • DOI: 10.1016/j.bbrc.2017.11.094
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Direct In Vivo Reprogramming with Sendai Virus Vectors Improves Cardiac Function after Myocardial Infarction. (2018)
  • Author(s): Miyamoto K, Akiyama M, Tamura F, Isomi M, Yamakawa H, Sadahiro T, Muraoka N, Kojima H, Haginiwa S, Kurotsu S, Tani H, Wang L, Qian L, Inoue M, Ide Y, Kurokawa J, Yamamoto T, Seki T, Aeba R, Yamagishi H, Fukuda K, Ieda M.
  • Journal Title: Cell Stem Cell. Volume: 4 Issue: 1 Pages: 91-103
  • DOI: 10.1016/j.stem.2017.11.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Real‐Time Analysis of the Heart Rate Variability During Incremental Exercise for the Detection of the Ventilatory Threshold (2018)
  • Author(s): Shiraishi Yasuyuki、Katsumata Yoshinori、Sadahiro Taketaro、Azuma Koichiro、Akita Keitaro、Isobe Sarasa、Yashima Fumiaki、Miyamoto Kazutaka、Nishiyama Takahiko、Tamura Yuichi、Kimura Takehiro、Nishiyama Nobuhiro、Aizawa Yoshiyasu、Fukuda Keiichi、Takatsuki Seiji
  • Journal Title: Journal of the American Heart Association Volume: 7 Issue: 1
  • DOI: 10.1161/jaha.117.006612
  • Peer Reviewed / Open Access
• [Journal Article] Single-Construct Polycistronic Doxycycline-Inducible Vectors Improve Direct Cardiac Reprogramming and Can Be Used to Identify the Critical Timing of Transgene Expression. (2017)
  • Author(s): Umei TC, Yamakawa H, Muraoka N, Sadahiro T, Isomi M, Haginiwa S, Kojima H, Kurotsu S, Tamura F, Osakabe R, Tani H, Nara K, Miyoshi H, Fukuda K, Ieda M.
  • Journal Title: Int J Mol Sci. Volume: 18 Issue: 8 Pages: 1805-1805
  • DOI: 10.3390/ijms18081805
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Tbx6 is Critical for Cardiac Mesoderm Induction and Lineage Specification Into Cardiovascular and Somite Lineages in Pluripotent Stem Cells (2018)
  • Author(s): Taketaro Sadahiro
  • Organizer: AHA
  • Int'l Joint Research
• [Presentation] Tbx6 Induces Cardiac Mesoderm Program in Fibroblasts and Pluripotent Stem Cells (2017)
  • Author(s): Taketaro Sadahiro, Mari Isomi, Naoto Muraoka, Kazutaka Miyamoto, Hiroyuki Yamakawa, Hidenori Kojima, Shou Haginiwa, Mizuha Akiyama, Yuki Kuishi, Shugo Tohyama, Hiroyuki Miyoshi, Yoshifumi Kawamura, Naoki Goshima, Keiichi Fukuda, Masaki Ieda.
  • Organizer: 日本循環器学会
  • Place of Presentation: 石川県立音楽堂(石川県金沢市)
  • Year and Date: 2017-03-18
• [Presentation] FactorX directly programs fibroblasts and pluripotent stem cells into cardiac mesodermal cells (2017)
  • Author(s): Taketaro Sadahiro
  • Organizer: AHA
  • Int'l Joint Research
• [Presentation] Tbx6 directly programs fibroblasts and pluripotent stem cells into cardiac mesodermal cells (2016)
  • Author(s): Taketaro Sadahiro, Mari Isomi, Naoto Muraoka, Kazutaka Miyamoto, Hiroyuki Yamakawa, Hidenori Kojima, Shou Haginiwa, Mizuha Akiyama, Yuki Kuishi, Shugo Tohyama, Hiroyuki Miyoshi, Yoshifumi Kawamura, Naoki Goshima, Keiichi Fukuda, Masaki Ieda.
  • Organizer: ＩＳＨＲ
  • Place of Presentation: 東京コンベンションホール(東京都中央区)
  • Year and Date: 2016-12-18