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Zhu, Wuqiang; Zhao, Meng; Mattapally, Saidulu; Chen, Sifeng; Zhang, Jianyi

CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes : Remuscularization of Injured Ventricle

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  • Medientyp: E-Artikel
  • Titel: CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell–Derived Cardiomyocytes : Remuscularization of Injured Ventricle : Remuscularization of Injured Ventricle
  • Beteiligte: Zhu, Wuqiang; Zhao, Meng; Mattapally, Saidulu; Chen, Sifeng; Zhang, Jianyi
  • Erschienen: Ovid Technologies (Wolters Kluwer Health), 2018
  • Erschienen in: Circulation Research
  • Sprache: Englisch
  • DOI: 10.1161/circresaha.117.311504
  • ISSN: 0009-7330; 1524-4571
  • Schlagwörter: Cardiology and Cardiovascular Medicine ; Physiology
  • Entstehung:
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  • Beschreibung: <jats:sec> <jats:title> <jats:underline>Rationale:</jats:underline> </jats:title> <jats:p>The effectiveness of transplanted, human induced pluripotent stem cell–derived cardiomyocytes (hiPSC-CMs) for treatment of ischemic myocardial injury is limited by the exceptionally low engraftment rate.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Objective:</jats:underline> </jats:title> <jats:p>To determine whether overexpression of the cell cycle activator CCND2 (cyclin D2) in hiPSC-CMs can increase the graft size and improve myocardial recovery in a mouse model of myocardial infarction by increasing the proliferation of grafted cells.</jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Methods and Results:</jats:underline> </jats:title> <jats:p> Human CCND2 was delivered to hiPSCs via lentiviral-mediated gene transfection. In cultured cells, markers for cell cycle activation and proliferation were ≈3- to 7-folds higher in CCND2-overexpressing hiPSC-CMs (hiPSC-CCND2 <jats:sup>OE</jats:sup> CMs) than in hiPSC-CMs with normal levels of CCND2 (hiPSC-CCND2 <jats:sup>WT</jats:sup> CMs; <jats:italic>P</jats:italic> &lt;0.01). The pluripotent genes (Oct 4, Sox2, and Nanog) decrease to minimal levels and undetectable levels at day 1 and 10 after differentiating to CMs. In the mouse myocardial infarction model, cardiac function, infarct size, and the number of engrafted cells were similar at week 1 after treatment with hiPSC-CCND2 <jats:sup>OE</jats:sup> CMs or hiPSC-CCND2 <jats:sup>WT</jats:sup> CMs but was about tripled in hiPSC-CCND2 <jats:sup>OE</jats:sup> CM–treated than in hiPSC-CCND2 <jats:sup>WT</jats:sup> CM–treated animals at week 4 ( <jats:italic>P</jats:italic> &lt;0.01). The cardiac function and infarct size were significantly better in both cell treatment groups’ hearts than in control hearts, which was most prominent in hiPSC-CCND2 <jats:sup>OE</jats:sup> CM–treated animals ( <jats:italic>P</jats:italic> &lt;0.05, each). No tumor formation was observed in any hearts. </jats:p> </jats:sec> <jats:sec> <jats:title> <jats:underline>Conclusions:</jats:underline> </jats:title> <jats:p>CCND2 overexpression activates cell cycle progression in hiPSC-CMs that results in a significant enhanced potency for myocardial repair as evidenced by remuscularization of injured myocardium. This left ventricular muscle regeneration and increased angiogenesis in border zone are accompanied by a significant improvement of left ventricular chamber function.</jats:p> </jats:sec>
  • Zugangsstatus: Freier Zugang