title: SDF-1 fused to a fractalkine stalk and a GPI anchor enables functional neovascularization.
abstract: The facilitated recruitment of vascular progenitor cells (VPCs) to ischemic areas might be a therapeutic target for neovascularization and repair. However, efficient and directed attraction of VPCs remains a major challenge in clinical application. To enhance VPC homing, we developed a fusion protein (S1FG), based on the biology of stroma-derived factor-1/CXCL12 and the mucin backbone taken from fractalkine/CXCL12. A GPI-anchor was included to link the fusion-protein to the cell surface. HUVECs transfected with S1FG were capable of increasing firm adhesion of CXCR4+-mononuclear cells (THP-1) under shear stress conditions in vitro. In an in vivo rabbit model of chronic hind limb ischemia, local S1FG application enhanced the recruitment of adoptively transferred embryonic EPCs (eEPCs) to the ischemic muscles 2.5-fold. S1FG combined with eEPC(low) (2 × 10(6)) yielded similar capillary growth as eEPC(high) (5 × 10(6)) alone. Compared to controls, collateral formation was increased in the S1FG eEPC(low) group, but not the eEPC(high) group without S1FG, whereas perfusion was found enhanced in both groups. In addition, S1FG also increased collateral formation and flow when combined with AMD3100 treatment, to increase circulating levels of endogenous VPC. These data demonstrate that the fusion protein S1FG is capable of enhancing the recruitment of exogenously applied or endogenously mobilized progenitor cells to sites of injury. Recombinant versions of S1FG applied via catheters in combination with progenitor cell mobilization may be useful in the treatment of chronic ischemic syndromes requiring improved perfusion.
authors.affiliation: Medizinische Klinik und Poliklinik I, Klinikum Großhadern, Ludwig-Maximilians-University and DZHK (German Centre for Cardiovascular Research), Partner Site Munich Heart Alliance, Munich, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Stachel
authors.forename: Teresa
authors.initials: T
authors.lastname: Trenkwalder
authors.forename: Franziska
authors.initials: F
authors.lastname: Götz
authors.forename: Chiraz
authors.initials: C
authors.lastname: El Aouni
authors.forename: Niklas
authors.initials: N
authors.lastname: Muenchmeier
authors.forename: Achim
authors.initials: A
authors.lastname: Pfosser
authors.forename: Claudia
authors.initials: C
authors.lastname: Nussbaum
authors.forename: Markus
authors.initials: M
authors.lastname: Sperandio
authors.forename: Antonis K
authors.initials: AK
authors.lastname: Hatzopoulos
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nelson
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
mesh_terms: D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D054428:Chemokine CX3CL1 / Q000378:metabolism*; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004705:Endocytosis / Q000187:drug effects; D017261:Glycosylphosphatidylinositols / Q000378:metabolism*; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D051379:Mice; D018919:Neovascularization, Physiologic / Q000187:drug effects*; D011817:Rabbits; D019718:Receptors, CXCR4 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism
chemical_list: D054428:Chemokine CX3CL1; D054377:Chemokine CXCL12; D017261:Glycosylphosphatidylinositols; D019718:Receptors, CXCR4; D011993:Recombinant Fusion Proteins
keywords: Arteriogenesis; CXCR4; Homing; Progenitor cells