As one of the least regenerative organs, the adult mammalian heart is incapable of replenishing lost myocardium following injury, making heart failure a substantial financial burden to the global healthcare system. Despite developments in medical therapies, devices, and cardiac transplantations, none have been able to reverse the loss of myocardial tissue and recovery of heart function. The overall lack of improvement in mortality rates and shortage of hearts for organ transplantations are key barriers in addressing the burden of heart failure. With the ability to generate high yields of cardiomyocytes and endothelial cells at low costs, along with the developments in cardiac tissue engineering, pluripotent stem cells are one of the most promising avenues being explored for treatment of heart failure.
Although several studies using different animal models have demonstrated benefits of transplanting these cells, one of the key hurdles have been the survival and retention of cells. This thesis has focused on two different approaches at enhancing the delivery and retention of cells. The first approach uses a naturally occurring fibrin based engineered heart tissue (EHT) in an intermediate sized animal model, the rabbit, due to many similarities to the human heart. As this model requires immunosuppression, the second approach has been to use immunocompromised mice with cells encapsulated in a printable and highly tuneable biomaterial, Polyhydroxyalkanoates (PHA) used as a scaffold. As both models have used a xenogeneic approach, the third chapter focuses on developing a syngeneic model of transplantation.
Transplantation of the EHT demonstrated improved cardiac function in the rabbit, as seen by increase in fractional area change and reduction in infarct size. Control hearts had a retention of ~20% at four weeks with a rapid and sustained neovascularisation of the patch and an increased proliferation of transplanted cardiomyocytes. The myocardially infarcted (MI) hearts on the other hand had a dramatic drop in retention attributed to an immune mediated cell loss. On the other hand, transplantation of stem cell derived cardiomyocytes and endothelial cells in PHA based scaffolds in the mouse model did not improve cardiac function. Although the patches were also neovascularised, retention of the cells was little to none at four weeks with evidence of mild immune response seen in the patches.
To develop a model to understand the effects of the xeno-reaction, the differentiation of syngeneic rabbit iPSCs was explored. Although promising differentiation towards the cardiac lineage was observed, a high efficiency differentiation into cardiomyocytes could not be achieved. With the feasibility and efficacy of transplanting stem cell derived cells explored in this thesis, the advantages, disadvantages, and hurdles towards cardiac regeneration have been made more obvious. This opens up avenues for future studies to develop models of cardiac tissue engineering closely resembling a clinical scenario.