Engineered biomaterials as extracellular microenvironments for guiding cell programming and reprogramming

The interface between cells and materials is a dynamic and complex environment where cells in contact with materials can sense their properties such as stiffness, matrix protein, and geometry and respond to these cues in multiple ways including through mechanical forces exerted on the matrix by the cells. Cells incorporate these cues via signal propagation through integrins, and translate this information through intracellular signal transduction cascades to regulate gene expression and cell fate decisions. Advances in biomaterials to direct stem cell lineage decisions have focused on designing biomimetic materials that realize the ‘‘in vivo” microenvironments’ ability to interact with cells. However, not only is designing tailored biomaterials that present multiple signals challenging, but the precise roles of physical and biochemical cues in coordinating cellular processes such as migration, proliferation, and differentiation remains difficult to dissect. After a short introduction we explore using model polyacrylamide hydrogel systems in Chapter 2-5 to study the effects of biophysical (elasticity and geometry) and chemical (matrix protein) cues on mesenchymal stem cell (MSC) fate decisions, showing these cues can play a large role in differentiation. In Chapter 6 we explore how switching the biophysical microenvironment (matrix stiffness and cell shape) can be used to understand the plasticity of MSC lineage specification. Finally, in Chapter 7-9, we demonstrate how geometric cues at the interface of tissue, where interfacial energy and curvature can be modulated in vitro, will dictate cancer cell tumorigenicity, metastatic potential, and the regulation of tumorangiogenesis. Moreover, we reveal a mechanism where perimeter features initiate α5β1 adhesion and epithelial-to-mesenchymal transition, Mitogen Activated Protein Kinase (MAPK) and Signal Transducer and Activator of Transcription (STAT) pathways, and regulation of distinct histone marks, to guide gene expression underlying the phenotypic alterations of malignant melanoma. Overall, we believe the work presented here demonstrates the importance and utility of extracellular properties in modulating cell programming and reprogramming, and should aid in the development of biomaterials for more efficiently directing distinct cellular states for the development of synthetic model systems that more accurately recapitulate the in vivo microenvironment