UC Berkeley

Until recently, adult mammals were not believed to maintain active neurogenesis into adulthood, and brains were thought to be fully formed and most-mitotic by the end of adolescence. However, it has recently been appreciated that continuous neurogenesis in mammals occurs in the subventricular and subgranular zones of the brain, and the ongoing process of neurogenesis has ramifications for mammalian learning, memory formation, and diseases such as Alzheimer's. They also serve as a potential reservoir for transplantation or stimulation therapies, where stem cells can repopulate and repair areas of the central nervous system damaged by disease or injury. However, in order to harness the potential of these cells and to understand the processes of learning and memory in mammals, we must first understand the deep molecular identities and pathways that govern stem cell fate specification and behavior. A growing body of literature has identified many factors that influence neural stem cell (NSC) differentiation, which includes soluble signals such as sonic hedgehog or VEGF or cell-cell signals such as Notch and ephrins. However, in addition to biochemical cues, mechanical properties of the stem cell niche such as substrate stiffness have also been found to contribute strongly to NSC fate specification.

A panel of studies were undertaken in order to determine the biological relevance of substrate stffness in NSC differentiation. We used atomic force microscopy to probe the natural stiffness variations and heterogeneities in the brain matrix, and then used these measurements to guide the synthesis of a dynamic, mechanically tunable hydrogel that allows for dynamic control of substrate stiffness. With this study, we identify a candidate molecular, YAP, that transduces information about extracellular elastic modulus to fate specification pathways within the cell – specifically, β-catenin. We then expand our model into a three-dimensional platform, and identify another signaling pathway critical for neurogenesis – CD44, a hyaluronan receptor molecule.

These discoveries improve our understanding of basic NSC mechanobiology, and reveal new target pathways for modulation in generating in vitro culture platforms or engineering NSCs for transplantation or stimulation therapies.