Circulating human CD34 + progenitor cells modulate neovascularization and inflammation in a nude mouse model

Abstract

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.