Transplantation Effectiveness of Induced Pluripotent Stem Cells Is Improved by a Fibrinogen Biomatrix in an Experimental Model of Ischemic Heart Failure.

Abstract

The aim of this study was to investigate whether a fibrinogen biomatrix improves the transplantation effectiveness of induced pluripotent stem cells (iPSCs) in a model of myocardial infarction. Early retention, engraftment, and cell proliferation are important factors for successful cardiac stem cell therapy. Common transplantation techniques involve the direction injection of cells in aqueous media. However, this approach yields low retention and variable cell biodistribution, leading to reduced grafts that are unable to sufficiently regenerate damaged myocardium. Biologically compatible scaffolds that improve the retention of injected cells can improve cardiac stem cell therapy. Murine iPSCs were transfected for luciferase reporter gene expression. First, in vitro experiments were performed comparing cell viability in fibrinogen and medium. Second, iPSCs were transplanted intramyocardially by direct injection into ischemic myocardium of immunodeficient mice, following permanent left coronary artery ligation. Cells were delivered in medium or fibrinogen. Follow-up included graft assessment by bioluminescence imaging, the evaluation of cardiac function by magnetic resonance imaging, and histology to evaluate graft size and determine the extent of myocardial scarring. In vitro experiments showed proliferation of iPSCs in fibrinogen from 6.4×10(3)±8.0×10(2) after 24 h to 2.1×10(4)±3.2×10(3) after 72 h. Early cardiac cell amount in control group animals was low (23.7%±0.7%) with massive cell accumulation in the right (46.3%±1.0%) and the left lung (30.0%±0.6%). When iPSCs were injected applying the fibrinogen biomatrix, intramyocardial cell amount was increased (66.3%±0.9%) with demonstrable graft proliferation over the experimental time course. Left ventricle-function was higher in the fibrinogen group (42.9%±2.8%), also showing a higher fraction of refilled infarcted-area (66.9%±2.7%). The fibrinogen biomatrix improved cardiac iPSc retention, sustaining functional improvement and cellular refill of infarcted myocardium. Therefore, fibrinogen can be considered an ideal biological scaffold for intramyocardial stem cell transplantations.