Journal
CIRCULATION RESEARCH
Volume 122, Issue 1, Pages 88-96Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCRESAHA.117.311504
Keywords
cell cycle; cyclin D2; induced pluripotent stem cells; myocardial infarction; regeneration
Funding
- National Institutes of Health National Heart, Lung, and Blood Institute [HL 95077, HL114120, HL131017, UO1 HL134168]
- American Heart Association Scientist Development grant
- China Scholarship Council grant
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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 approximate to 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.
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