title: Dual delivery of VEGF and MCP-1 to support endothelial cell transplantation for therapeutic vascularization.
abstract: Transplantation of endothelial cells (EC) for therapeutic vascularization is a promising approach in tissue engineering but has yet to be proven effective in clinical trials. This cell-based therapy is hindered by significant apoptosis of EC upon transplantation as well as poor recruitment of host mural cells to stabilize nascent vessels. Here, we address these deficiencies by augmenting endothelial cell transplantation with dual delivery of vascular endothelial growth factor (VEGF) - to improve survival of transplanted EC - and monocyte chemotactic protein-1 (MCP-1) - to induce mural cell recruitment. We produced alginate microparticles that deliver VEGF and MCP-1 with distinct release kinetics and that can be integrated into a collagen/fibronectin (protein) gel construct for delivery of EC. Combined delivery of VEGF and MCP-1 increased functional vessel formation from transplanted EC and also led to a higher number of smooth muscle cell-invested vessels than did EC therapy alone. Despite the well-known role of MCP-1 in inflammation, these beneficial effects were accomplished without a long-term increase in monocyte/macrophage recruitment or a shift to a pro-inflammatory (M1) macrophage phenotype. Overall, these data suggest a potential benefit of combined delivery of MCP-1 and VEGF from EC-containing hydrogels as a strategy for therapeutic vascularization.
authors.affiliation: Department of Biomedical Engineering, Yale University, New Haven, CT 06511, USA.
authors.forename: Steven M
authors.initials: SM
authors.lastname: Jay
authors.forename: Benjamin R
authors.initials: BR
authors.lastname: Shepherd
authors.forename: Jillian W
authors.initials: JW
authors.lastname: Andrejecsk
authors.forename: Themis R
authors.initials: TR
authors.lastname: Kyriakides
authors.forename: Jordan S
authors.initials: JS
authors.lastname: Pober
authors.forename: W Mark
authors.initials: WM
authors.lastname: Saltzman
mesh_terms: D000464:Alginates / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001808:Blood Vessels / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D002470:Cell Survival / Q000187:drug effects; D018932:Chemokine CCL2 / Q000008:administration & dosage / Q000494:pharmacology; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods; D042783:Endothelial Cells / Q000166:cytology / Q000187:drug effects* / Q000502:physiology / Q000637:transplantation*; D006801:Humans; D020100:Hydrogels / Q000737:chemistry / Q000378:metabolism; D020007:Implants, Experimental; D051379:Mice; D008863:Microspheres; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage / Q000494:pharmacology
chemical_list: D000464:Alginates; D018932:Chemokine CCL2; D004337:Drug Carriers; D020100:Hydrogels; D042461:Vascular Endothelial Growth Factor A