OBJECTIVE Vascular progenitor cells (VPCs), which are able to differentiate into both endothelial cells and smooth muscle cells, have the potential for treatment of ischemic diseases. Generated by pluripotent stem cells, VPCs carry the risk of tumorigenicity in clinical application. This issue could be resolved by direct lineage conversion, the induction of functional cells from another lineage by using only lineage-restricted transcription factors. Here, we show that induced VPCs (iVPCs) can be generated from fibroblasts by ETS (E-twenty six) transcription factors, Etv2 and Fli1. Approach and Results: Mouse fibroblasts were infected with lentivirus encoding Etv2 and Fli1. Cell colonies appeared in Fli1- and Etv2/Fli1-infected groups and were mechanically picked. The identity of cell colonies was confirmed by proliferation assay and reverse-transcription polymerase chain reaction with vascular markers. Etv2/Fli1- infected cell colonies were sorted by CD144 (CDH5, VE-cadherin). We defined that CD144-positive iVPCs maintained its own population and expanded stably at multiple passages. iVPCs could differentiate into functional endothelial cells and smooth muscle cells by a defined medium. The functionalities of iVPC-derived endothelial cells and smooth muscle cells were confirmed by analyzing LDL (low-density lipoprotein) uptake, carbachol-induced contraction, and tube formation in vitro. Transplantation of iVPCs into the ischemic hindlimb model enhanced blood flow without tumor formation in vivo. Human iVPCs were generated by ETV2 and FLI1. CONCLUSIONS We demonstrate that ischemic disease curable iVPCs, which have self-renewal and bipotency, can be generated from mouse fibroblasts by enforced ETS family transcription factors, Etv2 and Fli1 expression. Our simple strategy opens insights into stem cell-based ischemic disease therapy.

中文翻译：

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Etv2和Fli1诱导的血管祖细胞可增强缺血性血管疾病模型简要报告中的功能恢复。

目的血管祖细胞（VPC）能够分化为内皮细胞和平滑肌细胞，具有治疗缺血性疾病的潜力。VPC由多能干细胞产生，在临床应用中具有致癌性的风险。此问题可以通过直接谱系转换（仅使用谱系限制的转录因子从另一个谱系诱导功能细胞）来解决。在这里，我们显示诱导的VPC（iVPC）可以由ETS（E-26）转录因子Etv2和Fli1从成纤维细胞生成。方法和结果：小鼠成纤维细胞被编码Etv2和Fli1的慢病毒感染。细胞集落出现在Fli1和Etv2 / Fli1感染组，并被机械采摘。通过增殖测定和与血管标志物的逆转录聚合酶链反应来确认细胞集落的身份。Etv2 / Fli1感染的细胞集落按CD144（CDH5，VE-钙粘着蛋白）分类。我们定义CD144阳性iVPC维持其自身种群并在多次传代中稳定扩展。iVPC可通过定义的培养基分化为功能性内皮细胞和平滑肌细胞。iVPC衍生的内皮细胞和平滑肌细胞的功能通过分析LDL（低密度脂蛋白）摄取，卡巴胆碱引起的收缩和体外管形成来确认。iVPCs移植到缺血性后肢模型中可增强血流量，而不会在体内形成肿瘤。人iVPC由ETV2和FLI1生成。结论我们证明了缺血性疾病可治愈的iVPC，可以通过增强的ETS家族转录因子，Etv2和Fli1表达从小鼠成纤维细胞中产生具有自我更新和双能性的蛋白质。我们的简单策略为基于干细胞的缺血性疾病治疗开辟了见识。