TY - JOUR
T1 - CCND2 Overexpression Enhances the Regenerative Potency of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes
T2 - Remuscularization of Injured Ventricle
AU - Zhu, Wuqiang
AU - Zhao, Meng
AU - Mattapally, Saidulu
AU - Chen, Sifeng
AU - Zhang, Jianyi
N1 - Publisher Copyright:
© 2017 American Heart Association, Inc.
PY - 2018/1/5
Y1 - 2018/1/5
N2 - 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.
AB - 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.
KW - cell cycle
KW - cyclin D2
KW - induced pluripotent stem cells
KW - myocardial infarction
KW - regeneration
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U2 - 10.1161/CIRCRESAHA.117.311504
DO - 10.1161/CIRCRESAHA.117.311504
M3 - Article
C2 - 29018036
AN - SCOPUS:85040175911
SN - 0009-7330
VL - 122
SP - 88
EP - 96
JO - Circulation research
JF - Circulation research
IS - 1
ER -