van der Strate B W A, Popa E R, Schipper M, Brouwer L A, Hendriks M, Harmsen M C, van Luyn M J A
Department of Pathology and Laboratory Medicine, Medical Biology Section, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ Groningen, The Netherlands.
J Mol Cell Cardiol. 2007 Jun;42(6):1086-97. doi: 10.1016/j.yjmcc.2007.03.907. Epub 2007 Apr 4.
CD34+ progenitor cells hold promise for therapeutic neovascularization in various settings. In this study, the role of human peripheral blood CD34+ cells in neovascularization and inflammatory cell recruitment was longitudinally studied in vivo. Human CD34+ cells were incorporated in Matrigel, implanted subcutaneously in nude mice, and explanted after 2, 4, 7, or 14 days. Cell-free Matrigels served as controls. Histochemical analyses demonstrated that neovascularization occurred almost exclusively in CD34+ implants. Cellular and capillary density were increased in cell-loaded Matrigels after 2 days and further increased at 14 days. Human CD34+ cells did not incorporate in neovessels, but formed vWF+/CD31+/VEGF+ cell clusters that were present up to day 14. However, CD34+ cells induced host neovascularization, as demonstrated by increased presence of murine CD31+ and vWF+ vasculature from day 7 to 14. Moreover, recruitment of murine monocytes/macrophages was significantly enhanced in CD34+ implants at all time points. Gene expression of chemotactic cytokines MCP-1 and IL-8 was detected on CD34+ cells in vitro and confirmed immunohistochemically in cell-loaded explants at all time points. Our data indicate that human CD34+ cells, implanted in a hypoxic environment, generate an angiogenic niche by secreting chemotactic and angiogenic factors, enabling rapid neovascularization, possibly via recruitment of monocytes/macrophages.
CD34+祖细胞在多种情况下对治疗性血管新生具有潜在价值。在本研究中，对人外周血CD34+细胞在血管新生和炎性细胞募集方面的作用进行了体内纵向研究。将人CD34+细胞掺入基质胶中，皮下植入裸鼠体内，于2天、4天、7天或14天后取出。无细胞的基质胶作为对照。组织化学分析表明，血管新生几乎仅发生在CD34+植入物中。在加载细胞的基质胶中，细胞密度和毛细血管密度在2天后增加，并在14天时进一步增加。人CD34+细胞未掺入新生血管中，但形成了vWF+/CD31+/VEGF+细胞簇，这些细胞簇在第14天仍存在。然而，CD34+细胞可诱导宿主血管新生，从第7天到第14天，小鼠CD31+和vWF+脉管系统的出现增加即证明了这一点。此外，在所有时间点，CD34+植入物中鼠单核细胞/巨噬细胞的募集均显著增强。在体外检测到趋化细胞因子MCP-1和IL-8在CD34+细胞上的基因表达，并在所有时间点对加载细胞的植入物进行免疫组织化学证实。我们的数据表明，植入低氧环境中的人CD34+细胞通过分泌趋化因子和血管生成因子产生血管生成微环境，可能通过募集单核细胞/巨噬细胞实现快速血管新生。
