Hepatocyte Growth Factor‐Transfected Skeletal Myoblasts to Limit the Development of Postinfarction Heart Failure

Abstract

Stem cells transplanted to an injured heart affect the host myocardium indirectly. The cytokine hepatocyte growth factor (HGF) may play a key role in this paracrine activity. We hypothesized that HGF-overexpressing stem cells would restore cardiac function after myocardial infarction (MI). Because there is a high rate of cell death when injecting the cells intramyocardially, we used scaffold-based cell transfer. Skeletal myoblasts (SkMs) were isolated and expanded from newborn Lewis rats. Cells were transfected with pcDNA3-huHGF and seeded on polyurethane (PU) scaffolds or diluted in medium for cell injection. The seeded scaffolds were transplanted in rats two weeks after MI (group: PU-HGF-SkM) or the infection solution was intramyocardially injected (group: Inj-HGF-SkM). Two groups (Inj-SkM and PU-SkM) have been prepared with untransfected cells and sham group without any cell therapy served as control (n = 10 each group). At the beginning of treatment (baseline) and six weeks later, hemodynamic parameters were assessed. At the end of the study, histological analysis was employed. In sham animals we detected a decrease in systolic and diastolic function during the observation time. Treatment with untransfected myoblasts did not lead to any significant changes in hemodynamic parameters between the intervention and six weeks later. In group PU-HGF-SkM, systolic parameters like dP/dt(max), dP/dt(min) and isovolumic contraction improved significantly from baseline to study end. Some diastolic parameters were inferior as compared to baseline (SB-Ked, pressure half time [PHT], Tau). In group Inj-HGF-SkM, only PHT was impaired as compared to preinterventional values. Histological analysis showed significantly more capillaries in the infarction border zone in groups PU-HGF-SkM than in sham and Inj-SkM group. The infarction size was not affected by the therapy. Transplanting HGF-transfected myoblasts after MI can limit the development of ventricular dysfunction. Scaffold-based therapy in combination with gene therapy accelerates this capacity. This hemodynamic amelioration is accompanied by neovascularization, but not by smaller infarction sizes.

Heart regeneration after myocardial infarction using synthetic biomaterials

“…Nevertheless, statistical analysis showed no significant changes in infarct size between groups. Regarding cardiac function, only the HGF overexpressing SM-NFs treated group showed a significant improvement from baseline at the end of the study [94,95]. These results are in correlation with the study of Giraud M.N.…”

“…On one hand, von Wattenwyl R. et al used VEGF-overexpressing myoblasts (5x10 6 ) seeded on PU-NFs [94]. On the other hand, Poppe A. et al transfected SM (5x10 6 ) with HGF and then seeded them on the same DDS [95]. Apart from stimulating endothelial cell motility and enhancing angiogenesis, intramyocardial HGF secretion after ischemic injury was associated with less severe ventricular enlargement and with an improved cardiac function [96].…”

Activation of Diverse Signaling Pathways by Ex-Vivo Delivery of Multiple Cytokines for Myocardial Repair

“…Administration of HGF enhanced the efficacy of cell transplantation [28] and promoted cardiomyocyte proliferation in experimental animal models [29]. Furthermore, intramyocardial transplantation SM nonvirally modified for HGF expression has the capacity to limit infarct size expansion and cardiac dysfunction and these effects were accentuated by scaffold-based delivery of the cells [30]. (4) SDF-1a is a known ligand for CXCR4 receptors expressed on BMSC.…”

Artificial Organs 2012: A Year in Review

“…Annika Poppe et al. of the University Medical Center Freiburg, Freiburg, Germany reported on hepatocyte growth factor (HGF)‐transfected skeletal myoblasts (SkMs) to limit the development of postinfarction heart failure. SkMs were isolated and expanded from newborn Lewis rats, and the cells were transfected with pcDNA3‐huHGF and seeded on polyurethane (PU) scaffolds, or diluted in medium for cell injection.…”