Angiogenic Cell Therapy by Bone Marrow-Derived Monocyte-lineage Stem Cells

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Peripheral blood(PB)-derived CD14^+ monocytes were shown to trans-differentiate into endothelial cell(EC)-lineage cells and contribute to neovascularization. We investigated whether bone marrow(BM)- or PB-derived CD34^-/CD14^+ cells are involved in reendothelialization after carotid balloon injury. Human BM-derived CD34^-/CD14^+ monocyte-lineage cells (BM-MLCs), but not PB-derived CD34^-CD14^+ monocytes, expressed EC-specific markers (Tie2, CD31, VE-cadherin, Endoglin) to an extent identical to mature EC. When BM-MLCs were cultured with VEGF, hematopoietic markers were drastically decreased and new EC-specific markers (Flk and CD34) were induced. BM-MLCs were intra-arterially transplanted into balloon-injured arteries of athymic nude rats. Only when BM-MLCs were activated by MCP-1 in vivo or in vitro, they adhered onto injured endothelium, differentiated into EC-like cells by losing hematopoietic markers and inhibited neointimal hyperplasia. Such MCP-dependent adhesion was not observed in PB-derived CD34^-/CD14^+ monocytes. Regenerated endothelium exhibited cobble-stone appearance, blocked extravasation of dye and induced NO-dependent vasorelaxation. Basal adhesive activities on HUVEC under laminar flow and beta-1-integrin expression (basal and active forms) were significantly increased in BM-MLCs compared with PB-derived monocytes. MCP-1 markedly enhanced adhesive activity of BM-MLCs (2.8 fold) on HUVEC by activating beta-1-integrin conformation. Thus, BM-MLCs can function as EC progenitors and acquire the ability to adhere on injured endothelium in a MCP-1-dependent manner, leading to reendothelialization followed by inhibition of intimal hyperplasia. This will open a novel window to MCP-1-mediated biological actions as well as vascular regeneration strategies using BM cell therapy.