Rapid and Efficient Cardiac Direct Reprogramming using Sendai Virus Vectors

• Project/Area Number: 16K19428
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Cardiovascular medicine
• Research Institution: Keio University
• Principal Investigator: MIYAMOTO KAZUTAKA 慶應義塾大学, 医学部(信濃町), 共同研究員 (10528714)
• 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: 心筋再生 / direct reprogramming / センダイウイルス / 再生医療 / 直接誘導

Outline of Final Research Achievements

In this study, we show that Sendai virus (SeV) vectors expressing cardiac reprogramming factors efficiently and rapidly reprogram both mouse and human fibroblasts into integration-free iCMs via robust transgene expression. SeV-GMT generated 100-fold more beating iCMs than retroviral-GMT and shortened the duration to induce beating cells from 30 to 10 days in mouse fibroblasts. In vivo lineage tracing revealed that the gene transfer of SeV-GMT was more efficient than retroviral-GMT in reprogramming resident cardiac fibroblasts into iCMs in mouse infarct hearts. Moreover, SeV-GMT improved cardiac function and reduced fibrosis after myocardial infarction. Thus, efficient, non-integrating SeV vectors may serve as a powerful system for cardiac regeneration. Finally, we reported these result on one of authoritative scientific journals（Miyamoto et al., Cell Stem Cell 2017).

Academic Significance and Societal Importance of the Research Achievements

現在全世界において心臓疾患関連死は増加の一途をたどっており、新たな治療法の開発が望まれている。近年、iPS細胞をはじめとした再生医療は様々な領域において実用化に向けた検討がなされている。心疾患の分野においてもその臨床応用が開始されているが、依然として細胞の生着率の問題や安全性の面において克服すべき課題は多い。
その点において、本方法が臨床応用された場合上記のような問題点が一気に解消される可能性があり、学術的および社会的な意義は高いと考える。

Research Products

• [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
• [Presentation] Sendai Virus Vectors Achieve Mouse and Human Efficient Integration-Free Cardiac Reprogramming In Vitro and In Vivo (2018)
  • Author(s): Kazutaka Miyamoto
  • Organizer: The 82th annual meeting of Japanese Circulation Society
• [Presentation] Direct Reprogramming with Sendai Virus Vectors Improves Cardiac Function In Vitro and In Vivo (2018)
  • Author(s): Kazutaka Miyamoto
  • Organizer: The 2nd JCS Council Forum on Basic CardioVascular Research Award Session
• [Presentation] Efficient and Safe Cardiac Reprogramming using Sendai Viral Vectors (2017)
  • Author(s): Kazutaka Miyamoto
  • Organizer: 第81回日本循環器学会
  • Place of Presentation: 金沢市教育プラザ此花(石川県金沢市)
  • Year and Date: 2017-03-17
• [Presentation] Sendai Virus Vectors Achieve Efficient Integration-Free Cardiac Reprogramming In Vitro and In Vivo (2017)
  • Author(s): Kazutaka Miyamoto
  • Organizer: American Heart Association Scientific Sessions 2017
  • Int'l Joint Research
• [Presentation] Efficient and Safe Cardiac Reprogramming using Sendai Viral Vectors (2017)
  • Author(s): Kazutaka Miyamoto
  • Organizer: The 81th annual meeting of Japanese Circulation Society
• [Presentation] 自然免疫シグナル活性化を機序としたセンダイウイルスによる安全かつ効率的な心筋直接誘導法の確立 (2016)
  • Author(s): Kazutaka Miyamoto
  • Organizer: 第20回日本適応医学会
  • Place of Presentation: 東京コンベンションホール(東京都中央区)
  • Year and Date: 2016-12-16
• [Book] 心不全（第2版）上巻－最新の基礎・臨床研究の進歩－ (2018)
  • Author(s): 宮本和享, 家田真樹
  • Total Pages: 720
  • Publisher: 日本臨牀