Role of Wnt signaling in cardiomyocyte differentiation and its implication for the treatment of heart diseases

2013 Fiscal Year Final Research Report

• Project/Area Number: 21229010
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Circulatory organs internal medicine
• Research Institution: The University of Tokyo (2013); Osaka University (2010-2012); Chiba University (2009)
• Principal Investigator: KOMURO Issei 東京大学, 医学部附属病院, 教授 (30260483)
• Co-Investigator(Kenkyū-buntansha): NAGAI Toshio 千葉大学, 大学院・医学薬学府, 准教授 (00334194)
• Project Period (FY): 2009-05-11 – 2014-03-31
• Keywords: 循環器・高血圧 / 発生・分化 / Wntシグナル / iPS細胞 / 間葉系幹細胞 / 心不全

Research Abstract

Patients with heart diseases are increasing in number, and elucidation of the pathophysiology and development of novel therapeutic strategies for heart diseases are mandatory. Wnt signaling pathway plays multiple roles in development and diseases, and recent studies have also implicated Wnt signaling both in heart development during embryogenesis and heart diseases in the adult. In the present study, we have clarified the molecular mechanism how IGFBP4 inhibits Wnt signaling and promotes heart development. We have also identified that activation of Wnt signaling followed by inhibition of Wnt signaling by using small molecules can efficiently induce cardiac differentiation of human iPS cells and mouse mesenchymal stem cells. Finally, we have identified that complement protein C1q is increased in the serum of heart failure model mice and may play detrimental role in the progression of heart failure.

Research Products

• [Journal Article] Complement C1q activates canonical Wnt signaling and promotes aging-related phenotypes (2012)
  • Author(s): Naito AT, Sumida T, Nomura S, Liu ML, Higo T, Nakagawa A, Okada K, Sakai T, Hashimoto A, Hara Y, Shimizu I, Zhu W, Toko H, Katada A, Akazawa H, Oka T, Lee JK, Minamino T, Nagai T, Walsh K, Kikuchi A, Matsumoto M, Botto M, Shiojima I, Komuro I
  • Journal Title: Cell Volume: 149 Pages: 1298-1313
  • DOI: 10.1016/j.cell.2012.03.047
  • Peer Reviewed
• [Journal Article] Mitochondrial DNA that escapes from autophagy causes inflammation and heart failure (2012)
  • Author(s): Oka T, Hikoso S, Yamaguchi O, Taneike M, Takeda T, Tamai T, Oyabu J, Murakawa T, Nakayama H, Nishida K, Akira S, Yamamoto A, Komuro I, Otsu K
  • Journal Title: Nature Volume: 485 Pages: 251-255
  • DOI: 10.1038/nature10992
  • Peer Reviewed
• [Journal Article] A crucial role of activin A-mediated growth hormone suppression in mouse and human heart failure (2011)
  • Author(s): Fukushima N, Matsuura K, Akazawa H, Honda A, Nagai T, Takahashi T, Seki A, Murasaki KM, Shimizu T, Okano T, Hagiwara N, Komuro I
  • Journal Title: PLoS One Volume: 6 Pages: e27901
  • DOI: 10.1371/journal.pone.0027901
  • Peer Reviewed
• [Journal Article] Promotion of CHIP-mediated p53 degradation protects the heart from ischemic injury (2010)
  • Author(s): Naito AT, Okada S, Minamino T, Iwanaga K, Liu ML, Sumida T, Nomura S, Sahara N, Mizoroki T, Takashima A, Akazawa H, Nagai T, Shiojima I, Komuro I
  • Journal Title: Circ Res Volume: 106 Pages: 1692-1702
  • DOI: 10.1161/CIRCRESAHA.109.214346
  • Peer Reviewed
• [Journal Article] Transplantation of cardiac progenitor cells ameliorates cardiac dysfunction after myocardial infarction in mice (2009)
  • Author(s): Matsuura K, Honda A, Nagai T, Fukushima N, Iwanaga K, Tokunaga M, Shimizu T, Okano T, Kasanuki H, Hagiwara N, Komuro I
  • Journal Title: J Clin Invest Volume: 119 Pages: 2204-2217
  • DOI: 10.1172/JCI37456
  • Peer Reviewed
• [Presentation] Harmful Effects of Excessive Insulin Signaling in a Setting of Pressure Overload (2011)
  • Author(s): Issei Komuro
  • Organizer: American Heart Association 2011
  • Place of Presentation: Orlando, USA
  • Year and Date: 20111112-16
• [Presentation] Featured Lecture : Wnt Signaling and Age-Associated Diseases (2010)
  • Author(s): Issei Komuro
  • Organizer: Basic Cardiovascular Sciences 2010 Scientific Sessions
  • Place of Presentation: Rancho Mirage, USA
  • Year and Date: 20100719-22
• [Presentation] A novel cardiomyocyte differentiation factor (2010)
  • Author(s): Issei Komuro
  • Organizer: XXth World Congress of the International Society for Heart Research 2010 Kyoto
  • Place of Presentation: Kyoto, Japan
  • Year and Date: 20100513-16
• [Book] Novel therapeutic targets and stragegies against myocardial diseases In: Hill JA, Olson EN, eds. Muscle: Fundamental biology and mechanisms of disease. (2012)
  • Author(s): Naito AT, Shiojima I, Komuro I
  • Total Pages: 739-743
  • Publisher: Elsevier Inc.
• [Patent(Industrial Property Rights)] インスリン様増殖因子結合タンパク質を含有するWnt シグナル伝達阻害剤 (2009)
  • Inventor(s): 小室一成, 塩島一朗, 朱偉東
  • Industrial Property Rights Holder: 国立大学法人千葉大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: JP2009/058045
  • Filing Date: 2009-04-23
  • Overseas