(462e) Molecular Elucidation and Engineering of the Stem Cell Fate Decisions

Elucidating the mechanisms that govern stem cell self-renewal and differentiation is critical for understanding the roles these cells play in organismal development and function as well as for harnessing stem cells to repair tissues damaged by disease or injury.  It has become increasingly clear that stem cells are regulated not only by biochemical signals in the niche, but also by biophysical features in the way these signals are presented, though investigating the latter is challenged by experimental complexities in investigating and mimicking the complexity of the extracellular matrix (ECM), cell-cell interactions, and other niche components.  Recent work has demonstrated that bioactive, synthetic materials can be harnessed to emulate and thereby study the effects of solid phase, biophysical cues on cell function, and by extension to develop enhanced stem cell culture systems.  For example, activation of many cellular receptors involves the formation of oligomeric protein signaling complexes with ligands presented from the matrix, the surface of neighboring cells, and in some cases even from solution.  We have developed multivalent ligands – polymers conjugated to signaling proteins to yield biomimetic signals with nanoscale spatial organization – which potently induce the differentiation of human pluripotent stem cells in vitro and neural stem cells in vitro and in vivo.  In addition, these materials combined with optogenetics and super-resolution microscopy have yielded insights into signaling mechanisms that regulate the fate decisions of these cells.  Finally, such biomimetic materials can be integrated into safe, scaleable, fully defined, robust culture systems for pluripotent stem cell expansion and differentiation.