Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels
Direct reprogramming of fibroblasts into endothelial cells capable of angiogenesis and reendothelialization in tissue-engineered vessels
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DOI：
10.1073/pnas.1205526109
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发表时间：
2012-08-21
影响因子：
11.1
通讯作者：
Xu, Qingbo
中科院分区：
文献类型：
--
作者：
Margariti, Andriana;Winkler, Bernhard;Xu, Qingbo
诱导多能干（iPS）细胞的产生是再生医学的重要工具。然而，主要的限制是肿瘤发展的风险。在这项研究中，我们发现在体细胞重编程为多能状态的早期阶段，特定的基因表达模式发生了改变。因此，我们开发了一种通过将四种重编程因子（OCT4、SOX2、KLF4 和 c-MYC）转移到人成纤维细胞 4 d 来生成部分 iPS（PiPS）细胞的方法。 PiPS 细胞在体内不会形成肿瘤，并且清楚地显示出响应特定培养基和培养条件分化为内皮细胞 (EC) 的潜力。为了阐明 PiPS 细胞分化为 EC 的机制，确定了 SET 易位（骨髓性白血病相关）（SET）相似蛋白（SETSIP）在体细胞重编程过程中被诱导。重要的是，当 PiPS 细胞用 VEGF 处理时，SETSIP 转移到细胞核，直接与 VE-钙粘蛋白启动子结合，增加血管内皮钙粘蛋白 (VE-cadherin) 表达水平和 EC 分化。从功能上讲，PiPS-EC 改善了后肢缺血模型中的新血管形成和血流恢复。此外，当接种到脱细胞血管支架上时，PiPS-EC 表现出良好的附着性、稳定性、通畅性和典型的血管结构。这些发现表明，通过 SETSIP 和 VEGF 将成纤维细胞重编程为 ECs 具有潜在的临床应用。
The generation of induced pluripotent stem (iPS) cells is an important tool for regenerative medicine. However, the main restriction is the risk of tumor development. In this study we found that during the early stages of somatic cell reprogramming toward a pluripotent state, specific gene expression patterns are altered. Therefore, we developed a method to generate partial-iPS (PiPS) cells by transferring four reprogramming factors (OCT4, SOX2, KLF4, and c-MYC) to human fibroblasts for 4 d. PiPS cells did not form tumors in vivo and clearly displayed the potential to differentiate into endothelial cells (ECs) in response to defined media and culture conditions. To clarify the mechanism of PiPS cell differentiation into ECs, SET translocation (myeloid leukemia-associated) (SET) similar protein (SETSIP) was indentified to be induced during somatic cell reprogramming. Importantly, when PiPS cells were treated with VEGF, SETSIP was translocated to the cell nucleus, directly bound to the VE-cadherin promoter, increasing vascular endothelialcadherin (VE-cadherin) expression levels and EC differentiation. Functionally, PiPS-ECs improved neovascularization and blood flow recovery in a hindlimb ischemic model. Furthermore, PiPS-ECs displayed good attachment, stabilization, patency, and typical vascular structure when seeded on decellularized vessel scaffolds. These findings indicate that reprogramming of fibroblasts into ECs via SETSIP and VEGF has a potential clinical application.