Scaffold-Based Transplantation of Akt1-Overexpressing Skeletal Myoblasts: Functional Regeneration Is Associated with Angiogenesis and Reduced Infarction Size

Abstract

Myoblast-based therapy can improve cardiac function after infarction and is conventionally performed by direct injection. A scaffold-based transfer could overcome injection-associated problems. In upgrading this approach we transplanted skeletal myoblasts (SkM) overexpressing the prosurvival gene Akt1. SkM were transfected with pcDNA3-huda-Akt1 and seeded on polyurethane scaffolds. These scaffolds were transplanted in rats 2 weeks after myocardial infarction. Hemodynamics were analyzed before therapy and 6 weeks later. Infarction size and capillary density were performed thereafter. Additional groups received injections of Akt1-transfected or untransfected myoblasts, scaffolds seeded with untransfected myoblasts, or sham operation. Deterioration of global systolic left ventricular function could be inhibited by all therapeutic approaches. In addition, transplantation of Akt1-transfected cells, either scaffold-based or injected, was superior with regard to systolic properties of the left ventricular wall. This effect was accompanied by smaller infarction sizes and angiogenesis. Scaffolds with untransfected myoblasts yielded also smaller infarctions than injections of untransfected myoblasts. Both Akt groups profited with regard to dP/dt(min). In contrast, other diastolic parameters pointed at impaired relaxation and stiffer myocardium especially in the Akt1-scaffold group. In conclusion, SkM overexpressing Akt1 can maintain myocardial function after infarction, reduce infarction size, and induce neovascularization. Scaffold-based cell transfer does not augment this reverse remodeling capacity.

Functional regeneration of ischemic myocardium by transplanted cells overexpressing stromal cell-derived factor-1 (SDF-1): intramyocardial injection versus scaffold-based application

“…Previous studies suggested a scaffold-based application of transplanted cells to improve study outcome by avoiding cell loss due to injection, diffusion, or poor engraftment and by preventing injection-induced arrhythmias [18,24]. Unexpectedly, the scaffold-based application of SDF-1 expressing myoblasts to the infarcted heart did not further enhance the positive effects on systolic function observed in group Inj-SDF-1-SkM.…”

Stem cell death and survival in heart regeneration and repair

“…Interestingly, ECM-initiated survival signaling may be enhanced by direct introduction and overexpression of certain growth factor genes and downstream components of survival signaling pathway, e.g. protein kinase AKT [78]. Advantages, mechanisms and examples of cell transplantations either in aggregates or encapsulated in polymer coating or embedded in biocompatible ECM (hydrogels) have been recently reviewed by Sart and colleagues [79].…”

“…Although results of initial clinical trials using genetically engineered stem cell therapy are encouraging, many cell survival aspects need to be understood before this approach is fully applied in cardiac repair. A number of pro-survival proteins or angiogenic factors, including connexin Cx43, tumor necrosis factor receptor TNFR, stromal cell-derived factor-1 SDF-1, signaling kinase AKT1, ILK and growth factors HGF, FGF-4 and VEGF-A have been shown to contribute to repopulation of cells when overexpressed in an exact damaged site [78, 175, 209–211]. Other data showed that anti-apoptotic BCL-2 transgene expression can efficiently attenuate cardiomyoblast death early after transplantation [212], and that ERBB4 (erb-b2 receptor tyrosine kinase 4) overexpression potentiate MSC survival in the infarcted heart [213].…”

“…Genetic modification of MSCs with ILK been shown to promote cell survival and function of infarcted myocardium in vitro and in vivo [214]. Furthermore, it was demonstrated that cell adhesion benefit was quite negligible when compared with overexpression of AKT transgenes [78]. …”

Use of Artelon^® Cosmetic in soft tissue augmentation in dentistry

“…16 In some reports, Artelon membrane was precoated with laminin 10 µg/mL at room temperature and cell suspensions containing 5.0 × 10 6 cells were applied to the scaffold. 17 …”