| Popis: |
Current interventional, pharmacological and device therapies improve mortality and show a certain degree of efficacy in reversing pathological remodelling by impacting the fibrotic response following myocardial infarction. Despite this, the overall mortality rate for patients with chronic heart failure and sudden cardiac death remain high. For these reasons, there is an urgent unmet need for the development of novel therapeutic alternatives. Recently, there is a shifting focus to more specific targeting of the endogenous immune-stromal interplay and pathological fibrosis. It is in this context that work in this thesis investigated the potential of two different novel therapeutic strategies for cardiac repair: iPSC-derived MSCs and recombinant human platelet-derived growth factor (rhPDGF-AB). In the first phase of this work, we demonstrated that intramyocardial administration of iPSC-MSCs improved cardiac function compared to conventional BM-MSCs in a rodent model of MI without exhibiting a proarrhythmogenic effect. In the absence of engraftment, the therapeutic effects of Cymerus™ MSCs in vivo appear to be related to their ability to improve neovascularization via paracrine mechanisms. In the second phase of this work, we demonstrated that rhPDGF-AB promotes post-MI cardiac wound repair by altering the mechanics of the infarct scar and promoting vasculogenesis, resulting in robust cardiac functional improvement, decreased ventricular arrhythmias and improved survival. There is no doubt that altering the post-MI microenvironment to harness endogenous cardiac repair provides a framework to develop new therapeutic options. The work presented in this thesis demonstrates for the first time that both iPSC-derived MSCs and rhPDGF-AB exhibit a significant reparative potential. Due to manufacturing and scalability advantages, iPSC-MSC therapy offers the exciting opportunity for “off-the-shelf” stem cell therapy, rendering it an attractive cell type for cardiac repair. We believe that because it is possible to target cardiac scar with delivery of rhPDGF-AB, there is a strong translational potential for rhPDGF-AB as an adjunct to current MI treatment and possibly to modulate scar in other organs. |
