Controlled Release of Stromal Cell–Derived Factor-1alphaIn SituIncreases 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.

Genetic Enhancement of Stem Cell Engraftment, Survival, and Efficacy

“…For example, SDF-1 expression is expressed by the injured myocardium less than 1 week after myocardial infarction 5 and MCP-3 for less than 10 days. 14 Multiple studies have demonstrated that the delivery of SDF-1 to the myocardium either through cell-based gene therapy, 5,12,32,49 gene trans- fer, 50 or protein 51,52 leading to prolongation, or reestablishment of SDF-1 expression at times late after myocardial infarction leads to stem cell homing, an increase in vascular density, 5,32,49,53 activation and homing of cardiac stem cells, 55 and improvement in cardiac function. Furthermore, engineering of MSCs or HSCs to overexpress SDF-1 receptor CXCR4 similarly leads to greater homing of engineered MSCs and improved left ventricular function compared to control MSCs or HSCs when the cells were delivered within 24 hours of myocardial infarction.…”

Molecular mapping of the regenerative niche in a murine model of myocardial infarction

“…Controversial results have been reported on the expression of these genes in similar studies. CXCL12 is considered to play and important role in the recovery of MI (26)(27)(28)(29)(30)(31), but its expression in the infarcted heart or in the plasma is not always high. In rats, CXCL12 was detected 1 day after infarction, peaking on day 7 and declining to basal levels around 14 days later (32).…”

“…In humans, plasma levels of CXCL12 gradually decreased between 2, 7 and 60 days after MI (22). Although controversial, these studies do not alter the role that CXCL12 plays in the recovery of MI (26)(27)(28)(29)(30)(31). In a recent study, it was observed that the overexpression of CXCR4 (SDF-1 receptor) enhanced MSC recruitment and penetration into the ischemic regenerative niche, resulting in more efficient tissue repair (33).…”

Heart regeneration after myocardial infarction using synthetic biomaterials

“…Positive results were reported by Zhang G. et al, who reported that PEGylated fibrin NFs loaded with SDF-1 (100 ng), when injected in a mouse MI model, significantly increased myocardial recruitment of c-kit + cells compared to controls two weeks after treatment. Enhanced stem cell homing was maintained at 28 days, when LV function was significantly improved in comparison with the controls [100]. More recently, our group prepared smooth polymeric NFs of stat-modified PLGA to deliver NRG to the heart.…”