Transfected mesenchymal stem cells in a thermoreversible hydrogel matrix for the treatment of myocardial infarction

This research presented here was conducted for the purpose of finding an effective method of treating myocardial infarction utilizing genetically modified mesenchymal stem cells delivered in a thermoresponsive hydrogel. Heart disease is the most common cause of death in the industrialized world and treatment still has much room for improvement. Growth factor treatments have shown promise in revascularizing the infarcted tissue, provided either as a recombinant protein or by means of gene therapy. Stem cells are also a means of treating disease that is growing in effectiveness, although cells injected to the heart are often plagued by poor engraftment at the injection site. This research is divided into three main sections. The first deals with the selection of an appropriate growth factor to be used in the study. Testing included quantifying the pro-angiogenic effect of the multiple growth factors on human endothelial cells as well as the growth factors' effects on the proliferation of the cells. Plasmid DNA constructs for the growth factors of interest were created for use in these studies. Growth factors were also tested for their influence on the mesenchymal stem cells. It was found that none of the growth factors or polymers used for DNA complexation and transfection resulted in differentiation of the stem cells. After completing this phase of the research, platelet-derived growth factor "C" was chosen for use in the following phases of the work. The second phase dealt with the characterization of a scaffold to be used with the transfected stem cells. After injection of cells in saline to the myocardium, 90% of the cells can be lost from the injection site. The hydrogel PoligoGel© from Samyang Corp. was found to be compatible with the stem cells, being both nontoxic, as well as not affecting differentiation of the cells. The final portion of the research was the application of the growth factor, stem cells, and scaffold in vivo in a rat model to observe the effects of the treatment in the infarcted heart. Lewis rats underwent a coronary artery ligation to create an infarcted region of the heart. Stem cells transfected to express platelet-derived growth factor ‘C' were then injected into the heart in a thermoreversible scaffold. The effectiveness of the treatment was quantified by analyzing MRI scans of the heart, as well as the biodistribution of the injected cells. The biodistribution was performed by RT-PCR and showed a 15-fold increase in cells retained at the heart for groups injected with cells in a thermoreversible scaffold versus those injected in saline. The MRI data did not show any statistical significance between groups.