Human Cardiac Stem Cells With Reduced Notch Signaling Show Enhanced Therapeutic Potential in a Rat Acute Infarction Model

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  • Matsuda Takenori
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine Vascular Regeneration Research Group, Institute of Biomedical Research and Innovation
  • Miyagawa Shigeru
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
  • Fukushima Satsuki
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
  • Kitagawa-Sakakida Satoru
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine
  • Akimaru Hiroshi
    Vascular Regeneration Research Group, Institute of Biomedical Research and Innovation
  • Horii-Komatsu Miki
    Vascular Regeneration Research Group, Institute of Biomedical Research and Innovation
  • Kawamoto Atsuhiko
    Vascular Regeneration Research Group, Institute of Biomedical Research and Innovation
  • Saito Atsuhiro
    Medical Center for Translational Research, Osaka University Hospital
  • Asahara Takayuki
    Vascular Regeneration Research Group, Institute of Biomedical Research and Innovation Department of Regenerative Medicine Science, Tokai University School of Medicine
  • Sawa Yoshiki
    Department of Cardiovascular Surgery, Osaka University Graduate School of Medicine Medical Center for Translational Research, Osaka University Hospital

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Abstract

Background: Because human cardiac stem cells (CSC) have regeneration potential in damaged cardiac tissue, there is increasing interest in using them in cell-based therapies for cardiac failure. However, culture conditions, by which CSCs are expanded while maintaining their therapeutic potential, have not been optimized. We hypothesized that the plating cell-density would affect proliferation activity, differentiation and therapeutic potential of CSCs through the Notch signaling pathway. Methods and Results: Human CSCs were plated at 4 different densities. The population doubling time, C-KIT positivity, and dexamethasone-induced multidifferentiation potential were examined in vitro. The therapeutic potential of CSCs was assessed by transplanting them into a rat acute myocardial infarction (AMI) model. The low plating density (340cells/cm2) maintained the multidifferentiation potential with greater proliferation activity and C-KIT positivity in vitro. On the other hand, the high plating density (5,500cells/cm2) induced autonomous differentiation into endothelial cells by activating Notch signaling in vitro. CSCs cultured at low or high density with Notch signal inhibitor showed significantly greater therapeutic potential in vivo compared with those cultured at high density. Conclusions: CSCs cultured with reduced Notch signaling showed better cardiomyogenic differentiation and therapeutic potentials in a rat AMI model. Thus, reducing Notch signaling is important when culturing CSCs for clinical applications.  (Circ J 2014; 78: 222–231)<br>

Journal

  • Circulation Journal

    Circulation Journal 78 (1), 222-231, 2014

    The Japanese Circulation Society

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