title: Controlled release of stromal cell-derived factor-1 alpha in situ increases c-kit+ cell homing to the infarcted heart.
abstract: Stromal-derived factor 1alpha (SDF-1alpha) is a key stem cell homing factor that is crucial for mobilization of stem cells from bone marrow to peripheral blood and subsequent engraftment to the tissue of diseased organs. It has been reported that SDF-1alpha is transiently over-expressed in ischemic myocardium. Therefore, there may be a limited time window after acute myocardial infarction (AMI) during which stem cells are recruited to injured myocardium for repair. This study aimed at investigating whether controlled release of SDF-1alpha via a novel conjugated poly(ethylene glycol) (PEG) (PEGylated) fibrin patch at the infarct site would increase the rate of stem cell recruitment and offer potential therapeutic benefits. Recombinant mouse SDF-1alpha was covalently bound to the PEGylated fibrinogen as evidenced by immunoprecipitation and western blotting. The PEGylated fibrinogen, bound with recombinant mouse SDF-1alpha, was mixed with thrombin to form the PEGylated fibrin patch. The release kinetics of SDF-1alpha were detected in vitro using enzyme-linked immunosorbent assay. Using a mouse AMI model produced by a ligature on the left anterior descending coronary artery, a PEGylated fibrin patch bound with SDF-1alpha (100 ng) was placed on the surface of the infarct area of the left ventricle. Infarct size, left ventricular (LV) function, and the percentage of sca-1(+)/c-kit(+) cells within the infarct area were measured at days 7, 14, and 28 after AMI. In vitro results showed that SDF-1alpha was successfully bound to the PEGylated fibrin patch and can be released from the patch constantly for up to 10 days. Two weeks after infarction, the myocardial recruitment of c-kit(+) cells was significantly higher in the group treated with the SDF-1alpha PEGylated fibrin patch (n = 9) than in the AMI control group (n = 10) (p < 0.05; 11.20 +/- 1.71% vs. 4.22 +/- 0.96%, respectively). At day 28 post-AMI, unlike the control group, the group with the SDF-1alpha-releasing patch maintained stable release of SDF-1alpha concurrent with additional stem cell homing. Moreover, LV function was significantly better than in the control group. These data demonstrate that the PEGylated fibrin patch based SDF-1alpha delivery can improve the rate of c-kit(+) cell homing and improve LV function in hearts with postinfarction LV remodeling.
authors.affiliation: Department of Biomedical Engineering, University of Minnesota, Minneapolis, Minnesota 55455, USA.
authors.forename: Ge
authors.initials: G
authors.lastname: Zhang
authors.forename: Yasushiro
authors.initials: Y
authors.lastname: Nakamura
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Wang
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Hu
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Suggs
authors.forename: Jianyi
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000008:administration & dosage* / Q000502:physiology*; D003692:Delayed-Action Preparations; D005260:Female; D005340:Fibrinogen / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009203:Myocardial Infarction / Q000378:metabolism*; D009206:Myocardium / Q000378:metabolism*; D019009:Proto-Oncogene Proteins c-kit / Q000096:biosynthesis*
chemical_list: D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D003692:Delayed-Action Preparations; D005340:Fibrinogen; D019009:Proto-Oncogene Proteins c-kit