Induced pluripotent stem cell transplantation in the treatment of porcine chronic myocardial ischemia.
Induced pluripotent stem cell transplantation in the treatment of porcine chronic myocardial ischemia.
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DOI：
10.1016/j.athoracsur.2014.07.008
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发表时间：
2014-12
影响因子：
4.6
通讯作者：
Horvath, Keith A.
中科院分区：
文献类型：
--
作者：
Zhou, Yifu;Wang, Suna;Yu, Zuxi;Hoyt, Robert F., Jr.;Hunt, Timothy;Kindzelski, Bogdan;Shou, David;Xie, Wen;Du, Yubin;Liu, Chengyu;Horvath, Keith A.
本研究旨在观察诱导多能干细胞（iPSC）治疗慢性心肌缺血的效果。通过使用含有4种人因子（OCT 4、SOX 2、KLF 4和c-MYC）的慢病毒载体对第3代心肌成纤维细胞进行重编程。通过直接注射将P12-17的iPSC集落同种异体移植到10只猪的缺血心肌中。在注射后2、4、6、8和12周处死每组两只动物。在任何时间点均无明显的移植物抗宿主病体征。在2周时，在注射区域中检测到SSEA-4阳性iPSC的簇。在4至8周时，这些细胞开始增殖成被薄囊包围的小球体。12周时，细胞团仍存在，但大小和数量减少。这些肿块内的细胞是同质的，没有分化成任何特定谱系的迹象。与非注射区域相比，在iPSC簇内部和周围发现增加的平滑肌肌动蛋白或vWF阳性细胞。通过RT-PCR，与未处理区域相比，iPSC处理的心肌中VEGF、FGF和ANRT表达水平显著更高。这些结果表明，iPSC有助于血管生成。同种异体移植的猪iPSC在前两个月的缺血环境中增殖，并在免疫活性宿主中存活至少三个月。移植的iPSC也具有促血管生成作用，因此可能对缺血性心脏病具有有益作用。
This study was designed to test the effects of induced pluripotent stem cell (iPSC) in the treatment of chronic myocardial ischemia. The reprograming of passage 3 myocardial fibroblasts was performed by using the lentiviral vector containing 4 human factors: OCT4, SOX2, KLF4, and c-MYC. The iPSC Colonies at P12–17 were allogeneically transplanted into ischemic myocardium of ten swine by direct injection. Cohorts of two animals were sacrificed at 2, 4, 6, 8, and 12 weeks after injection. No signs of graft versus host disease were evident at any time points. At 2 weeks, clusters of SSEA-4-positive iPSCs were detected in the injected area. At 4 to 8 weeks, these cells started to proliferate into small spheres surrounded by thin capsules. At 12 weeks, the cell clusters still existed, but decreased in size and numbers. The cells inside these masses were homogeneous with no sign of differentiation into any specific lineage. Increased smooth muscle actin or vWF positive cells were found inside and around the iPSC clusters, compared with non-injected areas. By RT-PCR, the levels of VEGF, FGF, and ANRT expression were significantly higher in the iPSC treated myocardium compared to untreated areas. These results suggest that iPSCs contributed to angiogenesis. Allogeneically transplanted pig iPSCs proliferated despite an ischemic environment in first two months and survived for at least three months in immunocompetent hosts. Transplanted iPSCs were also pro-angiogenic and thus might have beneficial effects on the ischemic heart diseases.
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作者：
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