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

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

Research output: Contribution to journalArticlepeer-review

45 Scopus citations

Abstract

Rationale: 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. Objective: 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. Methods and Results: 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 OE CMs) than in hiPSC-CMs with normal levels of CCND2 (hiPSC-CCND2 WT CMs; P<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 OE CMs or hiPSC-CCND2 WT CMs but was about tripled in hiPSC-CCND2 OE CM-treated than in hiPSC-CCND2 WT CM-treated animals at week 4 (P<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 OE CM-treated animals (P<0.05, each). No tumor formation was observed in any hearts. Conclusions: 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.

Original languageEnglish (US)
Pages (from-to)88-96
Number of pages9
JournalCirculation research
Volume122
Issue number1
DOIs
StatePublished - Jan 5 2018

Keywords

  • cell cycle
  • cyclin D2
  • induced pluripotent stem cells
  • myocardial infarction
  • regeneration

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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