To repair the infarcted heart

Abstract

Many advances have been made in moving towards repairing the infarcted ischemic heart, but clinical translation remains challenging. It is unlikely that the solution of repairing the heart lies in a single factor targeting a single process. The main objective of the research in this thesis is to explore methods to protect the heart from ischemic and I/R injury and stimulate the innate reparative capacity of the heart to renew damaged myocardium. To provide scope to achieve these complex tasks, we subdivided the research into answering three consecutive questions: 1. How can we protect human cardiac cells from I/R injury? 2. How can we stimulate human cardiomyocytes to generate new functional cardiomyocytes to repair injured tissue? 3. If we have a protective and reparative therapy available, how can we deliver it safely and effectively to the right location in the heart? Chapter 2 focusses on the first step towards cardiac repair: limiting the damage inflicted during an ischemic event and reperfusion, the current golden standard of therapy. In this chapter we introduce a novel therapeutic factor that efficiently targets necroptotic cell death, a major form of cell death determining I/R injury. In Chapter 3, we develop a hiPSC-cardiomyocyte based platform to model human IHD. To do this, we assessed the role of metabolic maturation on susceptibility of hiPSC-cardiomyocytes to hypoxic damage. Chapter 4 discusses the potential of stimulating cardiomyocyte proliferation to regenerate the heart by focussing on the role of miRNA-128 in cardiac regeneration. Chapter 5 introduces the glycoprotein Follistatin-like 1 as a potential therapeutic tool to prevent cardiomyocyte cell death, increase vascularisation in the infarcted area and stimulate cardiomyocyte renewal. In Chapter 6, we used our model developed in chapter 3 to test the potential of Follistatin-like 1 as a therapeutic factor to treat human IHD. In Chapter 7, we discuss the role of non-coding RNAs in cardiac regeneration and vascularisation and how to provide localized and sustained delivery of non-coding RNAs to the infarcted region. Chapter 8 describes a new method we developed to assess the retention of injected hydrogels after cardiac injection using real-time tracking with radioactively labelled hydrogel subunits.Chapter 9 provides a summary and general discussion of the work presented in this thesis and discusses future directions.