Extracellular Matrix Elasticity Determines Stem Cell Fate Through Stretch-Activated Ion Channels

Extracellular matrix elasticity is a well-established determinant of lineage specification for many stem cell types. In neural stem cells, substrate stiffness controls glial versus neu-ronal specification. While matrix elasticity is known to be transduced at focal adhesion zones, the molecular mechanisms that direct mechanosensitive fate pathways are not well understood. Here we use a combination of electrophysiology, live cell microscopy and mo-lecular techniques to uncover a missing player in mechanosensitive lineage commitment. We find that human neural stem/progenitor cells (hNSPCs) express stretch-activated ion channels (SACs), whose activity triggers spontaneous, transient Ca2+ signals that are modu-lated by substrate stiffness. Pharmacological inhibition of SAC activity suppresses neuronal differentiation while promoting astrocyte formation, indicating that SACs are important for lineage choice. We will present results from an RNAi approach aimed at determining the molecular identity of the hNSPC SAC channel.