Piezo1 Transduces Extracellular Matrix Mechanical Cues to Direct Human Neural Stem Cell Fate

Abstract

Mechanical cues are powerful determinants of cell behavior. For instance, mechanical properties of the extracellular matrix direct neural stem cell fate, determining whether they differentiate along a neuronal or glial lineage. The molecular mechanisms linking matrix mechanics to intracellular signaling pathways that influence lineage choice remain unclear. Here we use a multi-disciplinary approach to uncover a new player in mechanosensitive lineage commitment.We find that the stretch-activated ion channel, Piezo1, generates a mechanically-induced ionic current in human neural stem/progenitor cells. In the absence of externally applied mechanical force, Piezo1 activity is elicited by cellular traction forces and manifests as spontaneous calcium transients that vary with substrate stiffness. Piezo1 knockdown evoked nuclear exclusion of the mechanoreactive transcriptional co-activator Yap, suggesting a downstream effector of channel activity. Suppression of Piezo1 activity by the pharmacological inhibitor GsMTx-4 or by siRNA-mediated knockdown reduced neurogenesis and enhanced astrogenesis, demonstrating a role for Piezo1 in neural stem cell fate.We propose that the mechanically-gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and that it may play similar roles in other multipotent stem cells.