Piezo1 is a mechanosensor of soft matrix viscoelasticity

Mechanosensitive ion channels, such as Piezo1, have emerged as having fundamental roles in sensing the mechanical properties of the extracellular matrix (ECM). However, whether and how Piezo1 senses time-dependent ECM mechanical properties, that is viscoelasticity, remains unknown. To address this question, we combined an immortalised mesenchymal stem cell (MSC) line in which Piezo1 expression can be silenced with soft and stiff viscoelastic hydrogels that have independently tuneable elastic and viscous moduli. We demonstrate that Piezo1 is a mechanosensor of viscoelasticity in soft ECMs, both experimentally and throughout simulations using a modified viscoelastic molecular clutch model that incorporates Piezo1. Using RNA sequencing, we also identify the transcriptomic phenotype of MSC response to matrix viscoelasticity and Piezo1 activity, identifying gene signatures that modulate MSC’s mechanobiology in soft and stiff viscoelastic hydrogels.