Biomaterials for the extracellular control of mesenchymal stem cell pro-angiogenic potential

With the prevalence of ischemic heart disease, cell based treatments have emerged as promising therapeutic options to promote angiogenesis. The use of adult mesenchymal stem cells (MSCs), particularly, is an area of active investigation. However, clinical efficacy has proved variable, likely on account of ill-defined cell delivery formulations and the inherent complexity of cellular secretion. The versatility of MSCs and their responsiveness to the environment make them very malleable to changes in the microenvironment. The use of well-defined biomaterials enables studying the influence of extracellular matrix properties on MSCs, which in turn gives criteria for the design of optimal biomaterials for therapeutic efficacy. After a short introduction we explore using model polyacrylamide hydrogel systems in Chapter 2 to study the effects of matrix elasticity and composition on MSC pro-angiogenic potential, showing elasticity can play a large role – dependent on matrix composition. In Chapter 3 we use micropatterning to reveal how changing cell shape (modulating cellular cytoskeleton, focal adhesions and contractility) can modulate not only the pro-angiogenic potential of MSCs but their phenotype and epigenetic state. We develop a biocompatible PEG-based hydrogel system in Chapter 4 and we show that this system can be used to spatially guide angiogenesis. Finally, in Chapter 5, we demonstrate a magnetoactive hydrogel system where mechanical properties can be modulated in vitro in order to study the effects of temporal changes in matrix properties, such as those that occur during infarction. Overall, we believe the work presented here demonstrates the importance and utility of extracellular properties in modulating stem cell behavior, especially in the context of cell-based therapies, and should aid in the development of biomaterials for the treatment of ischemic cardiovascular disease