(328d) 15d Plenary Lecture: Molecular Elucidation and Engineering of Stem Cell Niches

Stem cell microenvironments or niches present complex repertoires of signals to regulate the processes self-renewal and differentiation. There has been considerable progress in studying soluble signals that regulate stem cell function, but comparatively less work has focused on investigating the ?solid phase? of the microenvironment, in large part due to experimental complexities in manipulating matrix and other components. Recent work demonstrates that bioactive, synthetic materials can be harnessed to emulate and thereby study the effects of solid phase, biophysical cues on cell function. By using a modular, bioactive material, we have found that that the matrix modulus profoundly impacts neural stem cell self-renewal and differentiation, and mechanistic analysis implicates key mechanotransductive pathways in this process. Furthermore, immobilization of biochemical signals to the solid phase of a natural niche can lead to nanoscale organization of these signals, and nanostructured biological-polymeric conjugates likewise serve as potent effectors of neural stem and human embryonic stem cell function. For example, multimeric bioconjugates of the protein Sonic hedgehog that emulate the natural form are more potent in inducing the proliferation of adult neural stem cells and dopaminerigic neuronal differentiation of human embryonic stem cells. Finally, the combinatorial presentation of different matrix motifs from a material can generate synthetic systems capable of supporting the self-renewal and differentiation of both neural stem cells and human embryonic stem cells, thereby enabling the dissection or distillation of the ECM into key individual signals necessary to support stem cell function. Biomimetic materials can thus be employed to study mechanisms by which the solid phase of a stem cell microenvironment regulates cell function, as well as offer safe, scaleable, and robust systems to control stem cells for biomedical application.