Stretch-activated ion channel Piezo1 directs lineage choice in human neural stem cells

TLDR

Neural stem cells can differentiate into neurons, astrocytes, and oligodendrocytes, and lineage specification is highly sensitive to the mechanical properties of their environment, yet the molecular pathways linking matrix mechanics to intracellular signaling remain unclear. The study proposes that the mechanically gated ion channel Piezo1 is a key determinant of mechanosensitive lineage choice in neural stem cells and may have similar roles in other multipotent stem cells. Piezo1 is expressed in human neural stem/progenitor cells and mediates traction‑force–induced, substrate‑stiffness‑dependent Ca²⁺ influx, and inhibition or knockdown of Piezo1 suppresses neurogenesis, enhances astrogenesis, and reduces nuclear YAP localization.

Abstract

Neural stem cells are multipotent cells with the ability to differentiate into neurons, astrocytes, and oligodendrocytes. Lineage specification is strongly sensitive to the mechanical properties of the cellular environment. However, molecular pathways transducing matrix mechanical cues to intracellular signaling pathways linked to lineage specification remain unclear. We found that the mechanically gated ion channel Piezo1 is expressed by brain-derived human neural stem/progenitor cells and is responsible for a mechanically induced ionic current. Piezo1 activity triggered by traction forces elicited influx of Ca(2+), a known modulator of differentiation, in a substrate-stiffness-dependent manner. Inhibition of channel activity by the pharmacological inhibitor GsMTx-4 or by siRNA-mediated Piezo1 knockdown suppressed neurogenesis and enhanced astrogenesis. Piezo1 knockdown also reduced the nuclear localization of the mechanoreactive transcriptional coactivator Yes-associated protein. We propose that the mechanically gated ion channel Piezo1 is an important determinant of mechanosensitive lineage choice in neural stem cells and may play similar roles in other multipotent stem cells.