Popa Eliane R, Harmsen Martin C, Tio Rene A, van der Strate Barry W A, Brouwer Linda A, Schipper Martin, Koerts Jasper, De Jongste Mike J L, Hazenberg Aldert, Hendriks Marc, van Luyn Marja J A
Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Centre, University of Groningen, Room Z 2.7, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
J Mol Cell Cardiol. 2006 Jul;41(1):86-96. doi: 10.1016/j.yjmcc.2006.04.021. Epub 2006 Jun 14.
Within the phenotypically and functionally heterogeneous group of circulating progenitor cells (CPC), a subclass of cells with vascular repair potential have been identified. These CPC are detected and isolated based on single or combined expression of CD34, CD133 and VEGFR-2, and referred to as endothelial progenitor cells. Here we asked whether CPC subsets defined by single expression of these markers exhibit functional heterogeneity. As functional parameters, we chose the capacity of CPC to differentiate into endothelial cells. Moreover, we studied their role in remodeling by recruitment of inflammatory cells, an aspect that has been little explored. We established an in vivo model in which the intrinsic functional capacity of these human CPC subsets was studied. Human CD34+ CPC, but not CD133+ or VEGFR-2+ CPC, seeded in Matrigel pellets and transplanted subcutaneously in a nude mouse host, contributed little to donor-derived neovascularization. However, host angiogenesis in the Matrigel implant, as demonstrated by the presence of capillaries containing erythrocytes and expressing mouse CD31, was strong in response to implantation of human CD34+ CPC and significantly lower in response to the other two CPC subsets. Moreover, the CD34+ CPC subset was significantly superior to CD133+ CPC and VEGFR-2+ CPC in the recruitment of host monocytes/macrophages. These three CPC populations were further dissected into seven discrete subsets, based on three-parameter flow cytometry analysis of combined expression patterns of CD34, CD133 and VEGFR-2. In conclusion, in our system, CD34+ CPC contribute marginally to neovascularization by differentiation but are potent regulators of the host angiogenic and pro-inflammatory response, suggesting a possible role for these cells in the remodeling of vascular lesions.
在表型和功能各异的循环祖细胞（CPC）群体中，已鉴定出具有血管修复潜力的细胞亚类。这些CPC是根据CD34、CD133和VEGFR-2的单一或联合表达来检测和分离的，被称为内皮祖细胞。在此，我们探讨了由这些标志物单一表达所定义的CPC亚群是否表现出功能异质性。作为功能参数，我们选择了CPC分化为内皮细胞的能力。此外，我们研究了它们通过募集炎症细胞在重塑过程中的作用，这一方面此前鲜有研究。我们建立了一个体内模型，用于研究这些人类CPC亚群的内在功能能力。接种于基质胶微球并皮下移植到裸鼠宿主中的人类CD34⁺ CPC，而非CD133⁺或VEGFR-2⁺ CPC，对供体来源的新血管形成贡献甚微。然而，基质胶植入物中的宿主血管生成情况（通过含有红细胞并表达小鼠CD31的毛细血管的存在得以证明），在植入人类CD34⁺ CPC后很强，而对其他两个CPC亚群的反应则明显较低。此外，在募集宿主单核细胞/巨噬细胞方面，CD34⁺ CPC亚群显著优于CD133⁺ CPC和VEGFR-2⁺ CPC。基于CD34、CD133和VEGFR-2联合表达模式的三参数流式细胞术分析，这三个CPC群体进一步被细分为七个离散亚群。总之，在我们的系统中，CD34⁺ CPC通过分化对新血管形成的贡献很小，但却是宿主血管生成和促炎反应的有效调节因子，表明这些细胞在血管病变重塑中可能发挥作用。
