Molecular Elucidation and Engineering of the Stem Cell Fate Decisions

Stem cells are defined by their hallmark abilities to self-renew, or divide while in an immature state, and to differentiate into one or more specialized cell types. Elucidating the mechanisms that govern these fate decisions is critical for understanding the roles stem cells play in the development of organisms and maintenance of adult tissues, as well as for harnessing stem cells to repair organs damaged by disease or injury. Stem cell behaviors are strongly regulated by their microenvironment or niche, a specialized region of tissue that presents complex repertoires of signals. There has been considerable progress in studying important soluble biochemical signals, but comparatively less effort has been focused on investigating biophysical mechanisms by which the “solid phase” of the microenvironment regulates cell function, in large part due to experimental complexities in investigating and mimicking the complexity of the extracellular matrix (ECM), cell-cell interactions, 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. For example, by using modular, bioactive materials, we have found that material stiffness profoundly impacts neural stem cell and human embryonic stem cell self-renewal and differentiation, and mechanistic analysis implicates key mechanotransductive pathways in this process that are important in cell culture and in vivo. Furthermore, nanoscale spatial organization in the presentation of immobilized signals can modulate the activity of these signals, and nanostructured biological-polymeric conjugates likewise serve as potent effectors of neural stem and human embryonic stem cell function. Finally, the development of novel optogenetic tools offers capabilities to investigate signaling mechanisms involved in cell fate decisions. Biomimetic materials can thus be employed to study basic biophysical 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.