Department of Integrative Medical Sciences, Northeast Ohio Medical University, 4209 State Route 44, Rootstown, OH 44272, USA.
Circ Res. 2012 Jan 20;110(2):241-52. doi: 10.1161/CIRCRESAHA.111.250126. Epub 2011 Nov 17.
A well-developed coronary collateral circulation improves the morbidity and mortality of patients following an acute coronary occlusion. Although regenerative medicine has great potential in stimulating vascular growth in the heart, to date there have been mixed results, and the ideal cell type for this therapy has not been resolved.
To generate induced vascular progenitor cells (iVPCs) from endothelial cells, which can differentiate into vascular smooth muscle cells (VSMCs) or endothelial cells (ECs), and test their capability to stimulate coronary collateral growth.
We reprogrammed rat ECs with the transcription factors Oct4, Klf4, Sox2, and c-Myc. A population of reprogrammed cells was derived that expressed pluripotent markers Oct4, SSEA-1, Rex1, and AP and hemangioblast markers CD133, Flk1, and c-kit. These cells were designated iVPCs because they remained committed to vascular lineage and could differentiate into vascular ECs and VSMCs in vitro. The iVPCs demonstrated better in vitro angiogenic potential (tube network on 2-dimensional culture, tube formation in growth factor reduced Matrigel) than native ECs. The risk of teratoma formation in iVPCs is also reduced in comparison with fully reprogrammed induced pluripotent stem cells (iPSCs). When iVPCs were implanted into myocardium, they engrafted into blood vessels and increased coronary collateral flow (microspheres) and improved cardiac function (echocardiography) better than iPSCs, mesenchymal stem cells, native ECs, and sham treatments.
We conclude that iVPCs, generated by partially reprogramming ECs, are an ideal cell type for cell-based therapy designed to stimulate coronary collateral growth.
一个发达的冠状动脉侧支循环可以改善急性冠状动脉闭塞后患者的发病率和死亡率。虽然再生医学在刺激心脏血管生长方面具有巨大的潜力，但迄今为止，其结果喜忧参半，而且这种治疗的理想细胞类型尚未确定。
从内皮细胞中生成诱导的血管祖细胞（iVPCs），其可分化为血管平滑肌细胞（VSMCs）或内皮细胞（ECs），并测试其刺激冠状动脉侧支生长的能力。
我们用转录因子 Oct4、Klf4、Sox2 和 c-Myc 对大鼠 ECs 进行重编程。衍生出一个表达多能标志物 Oct4、SSEA-1、Rex1 和 AP 以及造血母细胞标志物 CD133、Flk1 和 c-kit 的重编程细胞群体。这些细胞被称为 iVPCs，因为它们仍然致力于脉管系统，并能在体外分化为血管 ECs 和 VSMCs。iVPCs 的体外血管生成潜力（二维培养的管网、生长因子减少的 Matrigel 中的管形成）优于天然 ECs。与完全重编程的诱导多能干细胞（iPSCs）相比，iVPCs 形成畸胎瘤的风险也降低了。当 iVPCs 被植入心肌时，它们与血管结合，增加冠状动脉侧支血流（微球），并改善心脏功能（超声心动图），优于 iPSCs、间充质干细胞、天然 ECs 和假手术治疗。
我们得出结论，通过部分重编程 ECs 生成的 iVPCs 是一种理想的细胞类型，可用于基于细胞的治疗，旨在刺激冠状动脉侧支生长。
