UC San Diego

Growth factor signaling is a key determinant of cellular decisions ranging from stem cell fate, to metabolic behavior. As such, gaining control over these signaling events is of critical importance to the field of regenerative medicine, which is continuously seeking novel means to tailor the cellular microenvironment to direct cells towards medically advantageous outcomes. Heparan sulfate (HS) glycosaminoglycans (GAGS) are sulfated polysaccharides found on the cell surface and in the extracellular matrix which are responsible for the engagement of growth factors as well as growth factor receptors as a means to spatiotemporally direct cell signaling events.Despite the obvious potential associated with controlling HS GAG-growth factor interactions, HS GAG-based approaches to manipulate cellular signaling has been minimal due to the complex nature of this class of sulfated polysaccharides. Sulfated GAGs like HS have a non-template driven synthesis, that is, their structure is not dictated by a genetic blue print. During assembly, the GAGs undergo a series of sulfations, isomerizations, and acetylations which give rise to their specific binding capacity, but it is this same complexity that poses a significant hurdle for synthetic or chemoenzymatic approaches geared at producing these structures for study and medical application. As a result, novel approaches must be developed to hone control over cell signaling using GAGs while circumventing the structural obstacle posed by the complexity of their structure. In this dissertation, I present a variety of accessible methods for the preparation of synthetic HS GAG mimetics, and demonstrate their efficacy in several contexts. In chapter 2, I introduce a HS GAG presenting, membrane incorporating, polymer which utilizes a multivalent display of commercially available HS GAG disaccharides to exert control over stem cell fate in a structure dependent manner. In chapter 3 I reveal the role of HS GAG in mesodermal differentiation. In chapter 4, I developed novel inhibitor of HS biosynthesis to arrest mESCs in a pluripotent state. Finally, in chapter 5, I reflect on the current state of HS mimetics and their use in stem cell biology.