Apoptosis-Resistant Cardiac Progenitor Cells Modified With Apurinic/Apyrimidinic Endonuclease/Redox Factor 1 Gene Overexpression Regulate Cardiac Repair After Myocardial Infarction
Apoptosis-Resistant Cardiac Progenitor Cells Modified With Apurinic/Apyrimidinic Endonuclease/Redox Factor 1 Gene Overexpression Regulate Cardiac Repair After Myocardial Infarction
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DOI：
10.5966/sctm.2015-0281
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发表时间：
2016-08-01
影响因子：
6
通讯作者：
Hasebe, Naoyuki
中科院分区：
文献类型：
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作者：
Aonuma, Tatsuya;Takehara, Naofumi;Hasebe, Naoyuki
克服细胞移植物的存活不足是基于细胞的治疗的基本目标。脱嘌呤/脱嘧啶核酸内切酶/氧化还原因子1（APE 1）促进细胞存活，并可能增强移植细胞的治疗效果。本研究的目的是确定APE 1在心脏祖细胞（CPC）中的过表达是否可以改善基于细胞的治疗的效率。用携带APE 1-DsRed的逆转录病毒（APE 1-CPC）或DsRed对照（对照CPC）感染从8 - 10周龄C57 BL/6小鼠心脏分离的CPC。然后在APE 1-CPC、对照CPC和与这些CPC共培养的新生大鼠心室肌细胞（NRVM）中评估氧化应激诱导的凋亡。该分析显示，APE 1过表达通过激活转化生长因子β激活激酶1（TAK1）和核因子（NF）-κ B抑制CPC凋亡。在共培养模型中，与对照组相比，APE 1-CPC在更大程度上抑制NRVM凋亡。此外，与对照CPC相比，APE 1-CPC移植到小鼠心肌梗死模型中后7天，存活的DsRed阳性CPC移植物的数量显著增加，并且在APE 1-CPC移植后28天，左心室射血分数显示出更大的改善，纤维化减轻。此外，7天后，与对照CPC相比，在注射APE 1-CPC的小鼠中观察到较少的炎性巨噬细胞和较高百分比的心脏α-肌节肌动蛋白阳性CPC移植物。总之，抗凋亡APE 1-CPC移植物增加了TAK1-NF-κ B通路的激活，在缺血心脏中有效存活，恢复了心脏功能，减少了心脏炎症和纤维化。CPC中APE 1过表达可能成为改善心脏细胞治疗的一种新策略。意义改善细胞移植物的存活对于最大化细胞治疗的功效至关重要。作者研究了缺血条件下APE 1在CPC中的作用，并评估了移植APE 1过表达CPC在心肌梗死小鼠模型中的治疗效果。APE 1在CPC移植物中阻碍了细胞凋亡，这些细胞凋亡部分是由于TAK 1-NF-κ B通路激活增加而引起的氧化应激。此外，在缺血心脏中有效存活的APE 1-CPC移植物通过多效性机制恢复了心脏功能并减轻了纤维化，这一机制仍有待表征。这些结果表明，APE 1在CPC中的过表达可能是一种新的策略，以加强心脏细胞治疗。
Overcoming the insufficient survival of cell grafts is an essential objective in cell-based therapy. Apurinic/apyrimidinic endonuclease/redox factor 1 (APE1) promotes cell survival and may enhance the therapeutic effect of engrafted cells. The aim of this study is to determine whether APE1 overexpression in cardiac progenitor cells (CPCs) could ameliorate the efficiency of cell-based therapy. CPCs isolated from 8- to 10-week-old C57BL/6 mouse hearts were infected with retrovirus harboring APE1-DsRed (APE1-CPC) or a DsRed control (control-CPC). Oxidative stress-induced apoptosis was then assessed in APE1-CPCs, control-CPCs, and neonatal rat ventricular myocytes (NRVMs) cocultured with these CPCs. This analysis revealed that APE1 overexpression inhibited CPC apoptosis with activation of transforming growth factor beta-activated kinase 1 (TAK1) and nuclear factor (NF)-kappa B. In the coculture model, NRVM apoptosis was inhibited to a greater extent in the presence of APE1-CPCs compared with control-CPCs. Moreover, the number of surviving DsRed-positive CPC grafts was significantly higher 7 days after the transplant of APE1-CPCs into a mouse myocardial infarction model, and the left ventricular ejection fraction showed greater improvement with attenuation of fibrosis 28 days after the transplant of APE1-CPCs compared with control-CPCs. Additionally, fewer inflammatory macrophages and a higher percentage of cardiac alpha-sarcomeric actinin-positive CPC-grafts were observed in mice injected with APE1-CPCs compared with control-CPCs after 7 days. In conclusion, antiapoptotic APE1-CPC graft, which increased TAK1-NF-kappa B pathway activation, survived effectively in the ischemic heart, restored cardiac function, and reduced cardiac inflammation and fibrosis. APE1 overexpression in CPCs may serve as a novel strategy to improve cardiac cell therapy.SIGNIFICANCEImproving the survival of cell grafts is essential to maximize the efficacy of cell therapy. The authors investigated the role of APE1 in CPCs under ischemic conditions and evaluated the therapeutic efficacy of transplanted APE1-overexpressing CPCs in a mouse model of myocardial infarction. APE1 hindered apoptosis in CPC grafts subjected to oxidative stress caused in part by increased TAK1-NF-kappa B pathway activation. Furthermore, APE1-CPC grafts that effectively survived in the ischemic heart restored cardiac function and attenuated fibrosis through pleiotropic mechanisms that remain to be characterized. These findings suggest that APE1 overexpression in CPCs may be a novel strategy to reinforce cardiac cell therapy.