Direct cardiac reprogramming by epigenetic factors and micro RNAs

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390216
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Circulatory organs internal medicine
• Research Institution: Keio University
• Principal Investigator: IEDA Masaki 慶應義塾大学, 医学部, 特任講師 (70296557)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 心臓 / マイクロＲＮＡ / 再生

Research Abstract

Direct reprogramming of fibroblasts into cells of interest holds great promise for regenerative medicine. Generation of cardiomyocyte-like cells from mouse fibroblasts was achieved by transduction of Gata4, Mef2c, and Tbx5 (GMT). However, the induction of fully reprogrammed functional cardiomyocytes is inefficient and the reprogramming mechanisms remain undefined. Here we demonstrate that cardiac microRNA promotes direct cardiac reprogramming from mouse embryonic fibroblasts (MEFs) and postnatal tail-tip fibroblasts. MiRNA overexpression with GMT transduction increased the generation rate of beating cardiomyocyte-like cells from MEFs by 7-fold compared to GMT alone, and shortened the duration to induce beating cells to 10 days. Molecularly, we found that fibroblast genes were suppressed early in reprogramming by miRNA overexpression. Thus, miRNA promotes direct cardiac reprogramming partly through silencing fibroblast signatures.

Research Products

• [Journal Article] Direct Reprogramming of Fibroblasts into Myocytes to Reverse Fibrosis (2014)
  • Author(s): Muraoka N, Ieda M
  • Journal Title: Annu Rev Physiol Volume: 76 Pages: 21-37
  • DOI: 10.1146/annurev-physiol-021113-170301
  • Peer Reviewed
• [Journal Article] Induction of Human Cardiomyocyte-like Cells from Fibroblasts by Defined Factors (2013)
  • Author(s): Wada R, Muraoka N, Inagawa K, Yamakawa H, Miyamoto K, Sadahiro T, Umei T, Kaneda R, Suzuki T, Kamiya K, Tohyama S, Yuasa S, Kokaji K, Aeba R, Yozu R, Yamagishi H, Kitamura T, Fukuda K, Ieda M
  • Journal Title: Proc Natl Acad Sci USA Volume: 110 (31) Pages: 12667-72
  • DOI: 10.1073/pnas.1304053110
  • Peer Reviewed
• [Journal Article] Srivastava D. Reprogramming of mouse fibroblasts into cardiomyocyte-like cells in vitro (2013)
  • Author(s): Qian L, Berry EC, Fu JD, Ieda M
  • Journal Title: Nat Protocol Volume: 8(6) Pages: 1204-15
  • DOI: 10.1038/nprot.2013.067
  • Peer Reviewed
• [Journal Article] Induction of Cardiomyocyte-like Cells in Infarct Hearts by Gene Transfer of Gata4, Mef2c, and Tbx5 (2012)
  • Author(s): Inagawa K, Miyamoto K, Yamakawa H, Muraoka N, Sadahiro T, Umei T, Wada R, Katsumata Y, Kaneda R, Nakade K, Kurihara C, Obata Y, Miyake K, Fukuda K, Ieda M
  • Journal Title: Circulation research Volume: 111 Pages: 1147-56
  • DOI: 10.1161/CIRCRESAHA.112.271148
  • Peer Reviewed
• [Journal Article] Critical factors for cardiac reprogramming (2012)
  • Author(s): Srivastava, D., and Ieda, M
  • Journal Title: Circulation research Volume: 111 Pages: 5-8
  • DOI: 10.1161/CIRCRESAHA.112.271452
  • Peer Reviewed
• [Presentation] Direct Reprogramming of Fibroblasts into Cardiomyocyte-like Cells in Infarct Hearts (2013)
  • Author(s): Masaki Ieda
  • Organizer: Stem Cell and Regenerative Medicine Global Congress 2013
  • Place of Presentation: Seoul, South Korea
  • Year and Date: 20130327-29
• [Presentation] 第77回日本循環器学会学術集会プレナリーセッション (2013)
  • Author(s): Masaki Ieda
  • Organizer: Direct Conversion of Fibroblasts into Cardiomyocyte-like Cells by Defined Factors
  • Place of Presentation: 横浜
  • Year and Date: 20130315-17
• [Presentation] 第48回日本小児循環器学会会長特別企画世紀の発見が医療を変える (2012)
  • Author(s): 家田真樹
  • Organizer: 直接リプログラミングによる心筋細胞の作製
  • Place of Presentation: 京都
  • Year and Date: 2012-07-05
• [Presentation] Direct Reprogramming of Fibroblasts into Functional Cardiomyocytes (2011)
  • Author(s): Masaki Ieda
  • Organizer: American Heart Association Scientific Sessions 2011, Pluripotent Stem Cell Biology
  • Place of Presentation: Orlando, Florida, USA
  • Year and Date: 20111112-16
• [Book] 直接リプログラミング技術を用いた再生医療の展望 (2014)
  • Author(s): 村岡直人, 家田真樹
  • Total Pages: 562-571
  • Publisher: 最新医学
• [Book] Taylor and Francis Group, Induced Cardiomyocytes : Direct reprogramming for cardiac regeneration "Cardiac Regeneration Using Stem Cells" USA (2013)
  • Author(s): Masaki Ieda
  • Total Pages: 258-275
  • Publisher: CRC Press
• [Book] Cellular Reprogramming and Fate Conversion "Advances in Stem Cell Research" USA (2012)
  • Author(s): Masaki Ieda
  • Total Pages: 211-225
  • Publisher: Humana Press, Springer
• [Remarks] 朝日新聞, 東京新聞, 毎日新聞, 日本経済新聞, 日経産業新聞, 産経新聞, 読売新聞, 日刊工業新聞, 中日新聞, TBSニュース, 時事通信, 共同通信, 日経バイオテク, 北海道新聞, 河北新報, 信濃毎日新聞, 静岡新聞, 沖縄タイムズ, 化学工業日報, 西日本新聞, 東奥日報, 北国新聞, 富山新聞, 北日本新聞, 大阪日日新聞, 山陽新聞, 日本海新聞, 大分合同新聞, 宮崎日日新聞, などに関連記事掲載『ヒトで心筋直接作製』2013年7月16日
• [Remarks] 朝日新聞, 日本経済新聞, 読売新聞, 産経新聞, 日経産業新聞, 日刊工業新聞, 東京新聞, 時事通信社, 共同通信社, 日経BP社, NHKニュース, ナショナルジオグラフィックニュース, などに関連記事掲載『移植せずに心筋再生慶大チーム心臓の細胞に遺伝子入れる方法開発』2012年8月29日