title: Vascular gene transfer of SDF-1 promotes endothelial progenitor cell engraftment and enhances angiogenesis in ischemic muscle.
abstract: Gene therapy approaches to enhance endothelial progenitor cell (EPC) homing may augment cell engraftment to ischemic tissue and lead to a greater therapeutic response. Therefore, we assessed the effects of ultrasound-mediated (UM) transfection of the chemokine stromal cell-derived factor-1 (SDF-1) on homing and engraftment of intravenously administered EPCs and the subsequent angiogenic response in chronically ischemic skeletal muscle. Bone marrow-derived EPCs were isolated from donor Fisher 344 rats, cultured and labeled in preparation for injection into recipient animals via a jugular vein. Using a model of chronic hindlimb ischemia in rats, we demonstrated that UM destruction of intravenous carrier microbubbles loaded with SDF-1 plasmid DNA resulted in targeted transfection of the vascular endothelium within ischemic muscle and greater local engraftment of EPCs. The combination of SDF-1gene therapy and EPCs lead to the greatest increase in tissue perfusion and microvascular density within ischemic muscle, compared to no treatment or either monotherapy alone. Our results demonstrate that UM transfection of SDF-1 improves EPC targeting to chronically ischemic tissue, enhancing vascular engraftment and leading to a more robust neovascularization response.
authors.affiliation: Division of Cardiology, Keenan Research Centre in Li Ka Shing Knowledge Institute, St Michael's Hospital, Toronto, Ontario, Canada.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Kuliszewski
authors.forename: Jeremy
authors.initials: J
authors.lastname: Kobulnik
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
authors.forename: Duncan J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: Howard
authors.initials: H
authors.lastname: Leong-Poi
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000235:genetics; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000378:metabolism*; D004730:Endothelium, Vascular / Q000503:physiopathology; D015316:Genetic Therapy; D006614:Hindlimb / Q000098:blood supply; D007511:Ischemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D018482:Muscle, Skeletal / Q000098:blood supply*; D018919:Neovascularization, Physiologic; D051381:Rats; D011916:Rats, Inbred F344; D013234:Stem Cells / Q000378:metabolism*; D014162:Transfection; D019737:Transplants
chemical_list: D054377:Chemokine CXCL12