5 years ago

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

Zhao, Zhu, Chen, Mattapally, Zhang
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 in hiPSC-CMs can increase the graft size and improve myocardial recovery in a mouse model of myocardial infarction (MI) by increasing the proliferation of grafted cells. Methods and Results: Human CCND2 was delivered to hiPSCs via lenti-viral mediated gene transfection. In cultured cells, markers for cell-cycle activation and proliferation were ~3-7 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, Nanog) decrease to minimal- and undetectable -levels at day 1 and 10 after differentiate to CMs. In the mouse MI 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 LV muscle regeneration and increased angiogenesis in border zone are accompanied by a significant improvement of LV chamber function.

Publisher URL: http://doi.org/10.1161/CIRCRESAHA.117.311504

DOI: 10.1161/CIRCRESAHA.117.311504

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