Identification of vascular progenitor cells from monkey ES cells and application for cell implantation therapy with search for novel vascular inducing factor

胚胎干细胞具有全能性和自我更新能力，作为再生医学的细胞来源，引起了研究者的广泛关注。我们曾报道，小鼠ES细胞来源的VEGF受体Flk-1阳性细胞在体外可分化为内皮细胞和血管平滑肌细胞（VSMC），构建血管，并将其命名为“血管祖细胞（VPC）"。本研究以ES细胞来源的VPC在血管再生医学中的临床应用为目标，对猴ES细胞来源的VPC进行了鉴定。与小鼠ES细胞不同，未分化的猴ES细胞表达Flk-1。Flk-1细胞在含有VEGF的胶原IV包被的培养皿上的分化诱导Flk-1 +、碱性磷酸酶-细胞，其可以分化为内皮细胞和VSMC以构建血管结构。我们还研究了ES细胞衍生的VPC用于植入以在体内再生血管的有用性。在肿瘤血管生成模型中，经VEGF和血清诱导分化的VPC可有效促进血管生成，并显著增加局部血流量，提示ES细胞源性VPC具有潜在的治疗应用价值。

ES cells with totipotency and self-renewal attract many investigators' attention as promising cell sources for regeneration medicine. We previously reported that Flk-1, one of VEGF receptors, -positive cells derived from mouse ES cells can be differentiated into endothelial cells and vascular smooth muscle cells (VSMC) to construct blood vessels in vitro and named them as "vascular progenitor cells (VPC)". In this research, to aim at clinical application of ES cells-derived VPC to vascular regeneration medicine, we identified VPC in monkey ES cells. Undifferentiated monkey ES cells express Flk-1, unlike mouse ES cells. Differentiation of Flk-1 cells on collagen IV-coated dishes with VEGF induced Flk-1 +, alkaline phosphatase - cells, which can be differentiated into endothelial cells ad VSMC to construct blood vessel structures. We also examined the usefulness of ES cells-derived VPC for implantation to regenerate blood vessels in vivo. Implanted VPC differentiated with VEGF and serum in tumor angiogenesis model effectively contributed to neoangiogenesis and significantly augmented local blood flow, which suggests potentials of therapeutic application of ES cells-derived VPC.