Cardiology Division, Department of Medicine, Queen Mary Hospital, the University of Hong Kong, Hong Kong, HKSAR, China.
PLoS One. 2013;8(3):e57876. doi: 10.1371/journal.pone.0057876. Epub 2013 Mar 5.
Functional endothelial-like cells (EC) have been successfully derived from different cell sources and potentially used for treatment of cardiovascular diseases; however, their relative therapeutic efficacy remains unclear. We differentiated functional EC from human bone marrow mononuclear cells (BM-EC), human embryonic stem cells (hESC-EC) and human induced pluripotent stem cells (hiPSC-EC), and compared their in-vitro tube formation, migration and cytokine expression profiles, and in-vivo capacity to attenuate hind-limb ischemia in mice. Successful differentiation of BM-EC was only achieved in 1/6 patient with severe coronary artery disease. Nevertheless, BM-EC, hESC-EC and hiPSC-EC exhibited typical cobblestone morphology, had the ability of uptaking DiI-labeled acetylated low-density-lipoprotein, and binding of Ulex europaeus lectin. In-vitro functional assay demonstrated that hiPSC-EC and hESC-EC had similar capacity for tube formation and migration as human umbilical cord endothelial cells (HUVEC) and BM-EC (P>0.05). While increased expression of major angiogenic factors including epidermal growth factor, hepatocyte growth factor, vascular endothelial growth factor, placental growth factor and stromal derived factor-1 were observed in all EC cultures during hypoxia compared with normoxia (P<0.05), the magnitudes of cytokine up-regulation upon hypoxic were more dramatic in hiPSC-EC and hESC-EC (P<0.05). Compared with medium, transplanting BM-EC (n = 6), HUVEC (n = 6), hESC-EC (n = 8) or hiPSC-EC (n = 8) significantly attenuated severe hind-limb ischemia in mice via enhancement of neovascularization. In conclusion, functional EC can be generated from hECS and hiPSC with similar therapeutic efficacy for attenuation of severe hind-limb ischemia. Differentiation of functional BM-EC was more difficult to achieve in patients with cardiovascular diseases, and hESC-EC or iPSC-EC are readily available as "off-the-shelf" format for the treatment of tissue ischemia.
已成功从不同细胞来源中获得功能性内皮样细胞（EC），并可能将其用于治疗心血管疾病；然而，其相对治疗效果尚不清楚。我们从人骨髓单核细胞（BM-EC）、人胚胎干细胞（hESC-EC）和人诱导多能干细胞（hiPSC-EC）中分化出功能性 EC，并比较了它们在体外的管状形成、迁移和细胞因子表达谱，以及在体内减轻小鼠后肢缺血的能力。只有 1/6 名严重冠状动脉疾病患者的 BM-EC 成功分化。然而，BM-EC、hESC-EC 和 hiPSC-EC 表现出典型的鹅卵石形态，能够摄取 DiI 标记的乙酰化低密度脂蛋白，并结合荆豆凝集素。体外功能测定表明，hiPSC-EC 和 hESC-EC 的管状形成和迁移能力与脐静脉内皮细胞（HUVEC）和 BM-EC 相似（P>0.05）。与常氧相比，所有 EC 培养物在缺氧条件下，主要血管生成因子（包括表皮生长因子、肝细胞生长因子、血管内皮生长因子、胎盘生长因子和基质衍生因子-1）的表达增加（P<0.05），而 hiPSC-EC 和 hESC-EC 中细胞因子的上调幅度更大（P<0.05）。与培养基相比，移植 BM-EC（n=6）、HUVEC（n=6）、hESC-EC（n=8）或 hiPSC-EC（n=8）可通过增强新生血管化显著减轻小鼠严重后肢缺血。总之，功能性 EC 可从 hESCs 和 hiPSC 中获得，对严重后肢缺血的治疗效果相似。在心血管疾病患者中，功能性 BM-EC 的分化更难实现，而 hESC-EC 或 iPSC-EC 可作为“现成”的治疗组织缺血的方法。
