Shmelkov Sergey V, Meeus Sarah, Moussazadeh Nelson, Kermani Pouneh, Rashbaum William K, Rabbany Sina Y, Hanson Marilee A, Lane William J, St Clair Ryan, Walsh Kathryn A, Dias Sergio, Jacobson Jason T, Hempstead Barbara L, Edelberg Jay M, Rafii Shahin
Weill Medical College of Cornell University, Division of Hematology-Oncology, New York, NY 10021, USA.
Circulation. 2005 Mar 8;111(9):1175-83. doi: 10.1161/01.CIR.0000157155.44008.0F.
CD133 (AC133) is a surface antigen that defines a broad population of stem cells, including myogenic and endothelial progenitors. CD133+ cells are rare in adult tissues, and the factors that support their differentiation into mature angiomyogenic cells are not known. These hurdles have hampered the use of CD133+ cells for therapeutic purposes. Because human fetal liver is a rich source of CD133+ cells, we sought to identify the growth factors that promote codifferentiation of these cells into angiogenic and myogenic cells.
Human fetal liver CD133+ and CD133- cell subpopulations were cultured with 5'-azacytidine or vascular endothelial growth factor (VEGF165) and/or brain-derived nerve growth factor (BDNF). CD133+ but not CD133- cells from human fetal liver codifferentiated into spindle-shaped cells, as well as flat adherent multinucleated cells capable of spontaneous contractions in culture. The resulting spindle-shaped cells were confirmed to be endothelial cells by immunohistochemistry analysis for von Willebrand factor and by acetylated LDL uptake. Multinucleated cells were characterized as striated muscles by electron microscopy and immunohistochemistry analysis for myosin heavy chain. Presence of VEGF165 and BDNF significantly enhanced angiomyogenesis in vitro. Inoculation of cells derived from CD133+ cells, but not CD133- cells, into the ear pinna of NOD/SCID mice resulted in the formation of cardiomyocytes, as identified by immunostaining with cardiac troponin-T antibody. These cells generated electrical action potentials, detectable by ECG tracing.
CD133 defines a population of human fetal liver cells capable of differentiating into both angiogenic and myogenic cells. Preconditioning of these CD133+ cells with VEGF165 and BDNF enhances the angiomyogenesis. CD133+ fetal liver cells ultimately may be used for therapeutic angiomyogenesis.
CD133（AC133）是一种表面抗原，可定义包括肌源性和内皮祖细胞在内的广泛干细胞群体。CD133+细胞在成体组织中罕见，且支持其分化为成熟血管肌生成细胞的因素尚不清楚。这些障碍阻碍了CD133+细胞用于治疗目的。由于人胎肝是CD133+细胞的丰富来源，我们试图确定促进这些细胞共分化为血管生成和肌生成细胞的生长因子。
用人胎肝CD133+和CD133-细胞亚群与5'-氮杂胞苷或血管内皮生长因子（VEGF165）和/或脑源性神经生长因子（BDNF）一起培养。人胎肝的CD133+而非CD133-细胞共分化为纺锤形细胞以及在培养中能够自发收缩的扁平贴壁多核细胞。通过对血管性血友病因子的免疫组织化学分析以及乙酰化低密度脂蛋白摄取，证实所得的纺锤形细胞为内皮细胞。通过电子显微镜和对肌球蛋白重链的免疫组织化学分析，将多核细胞鉴定为横纹肌。VEGF165和BDNF的存在显著增强了体外血管肌生成。将源自CD133+细胞而非CD133-细胞的细胞接种到NOD/SCID小鼠的耳廓中，通过心肌肌钙蛋白-T抗体免疫染色鉴定，结果形成了心肌细胞。这些细胞产生了可通过心电图描记检测到的电动作电位。
CD133定义了一群能够分化为血管生成和肌生成细胞的人胎肝细胞。用VEGF165和BDNF对这些CD133+细胞进行预处理可增强血管肌生成。CD133+胎肝细胞最终可能用于治疗性血管肌生成。
