Department of Medicine, Division of Cardiology, Stanford University School of Medicine, Stanford, CA 94305, USA.
Circ Res. 2012 Sep 14;111(7):882-93. doi: 10.1161/CIRCRESAHA.112.269001. Epub 2012 Jul 19.
Induced pluripotent stem cells (iPSCs) hold great promise for the development of patient-specific therapies for cardiovascular disease. However, clinical translation will require preclinical optimization and validation of large-animal iPSC models.
To successfully derive endothelial cells from porcine iPSCs and demonstrate their potential utility for the treatment of myocardial ischemia.
Porcine adipose stromal cells were reprogrammed to generate porcine iPSCs (piPSCs). Immunohistochemistry, quantitative PCR, microarray hybridization, and angiogenic assays confirmed that piPSC-derived endothelial cells (piPSC-ECs) shared similar morphological and functional properties as endothelial cells isolated from the autologous pig aorta. To demonstrate their therapeutic potential, piPSC-ECs were transplanted into mice with myocardial infarction. Compared with control, animals transplanted with piPSC-ECs showed significant functional improvement measured by echocardiography (fractional shortening at week 4: 27.2±1.3% versus 22.3±1.1%; P<0.001) and MRI (ejection fraction at week 4: 45.8±1.3% versus 42.3±0.9%; P<0.05). Quantitative protein assays and microfluidic single-cell PCR profiling showed that piPSC-ECs released proangiogenic and antiapoptotic factors in the ischemic microenvironment, which promoted neovascularization and cardiomyocyte survival, respectively. Release of paracrine factors varied significantly among subpopulations of transplanted cells, suggesting that transplantation of specific cell populations may result in greater functional recovery.
In summary, this is the first study to successfully differentiate piPSCs-ECs from piPSCs and demonstrate that transplantation of piPSC-ECs improved cardiac function after myocardial infarction via paracrine activation. Further development of these large animal iPSC models will yield significant insights into their therapeutic potential and accelerate the clinical translation of autologous iPSC-based therapy.
诱导多能干细胞（iPSC）为心血管疾病的患者特异性治疗的发展带来了巨大的希望。然而，临床转化将需要对大型动物 iPSC 模型进行临床前优化和验证。
成功地从猪诱导多能干细胞中诱导出内皮细胞，并证明其在治疗心肌缺血方面的潜在应用。
猪脂肪基质细胞被重编程以产生猪诱导多能干细胞（piPSC）。免疫组织化学、定量 PCR、微阵列杂交和血管生成测定证实，piPSC 衍生的内皮细胞（piPSC-ECs）与从自体猪主动脉分离的内皮细胞具有相似的形态和功能特性。为了证明其治疗潜力，将 piPSC-EC 移植到心肌梗死的小鼠体内。与对照组相比，移植了 piPSC-EC 的动物在超声心动图（第 4 周时的分数缩短：27.2±1.3%对 22.3±1.1%；P<0.001）和 MRI（第 4 周时的射血分数：45.8±1.3%对 42.3±0.9%；P<0.05）方面表现出显著的功能改善。定量蛋白分析和微流控单细胞 PCR 分析显示，piPSC-EC 在缺血微环境中释放了促血管生成和抗凋亡因子，分别促进了血管新生和心肌细胞存活。移植细胞亚群之间的旁分泌因子释放差异很大，这表明移植特定细胞群可能会导致更大的功能恢复。
总之，这是第一项成功地从 piPSC 中诱导出 piPSC-ECs 并证明移植 piPSC-ECs 通过旁分泌激活改善心肌梗死后心功能的研究。进一步开发这些大型动物 iPSC 模型将深入了解其治疗潜力，并加速自体 iPSC 为基础的治疗的临床转化。
