Pressure sensing through Piezo channels controls whether cells migrate with blebs or pseudopods

Area of Science:

• Cell Biology
• Biophysics
• Mechanobiology

Background:

• Cell migration is essential for development and disease.
• Cells utilize blebs and pseudopods for motility, with blebs often preferred in mechanically resistant environments like tissues.
• The mechanisms by which cells sense and respond to mechanical forces during migration are not fully understood.

Purpose of the Study:

• To investigate how migrating cells detect and respond to mechanical forces, specifically uniaxial pressure.
• To elucidate the molecular pathways involved in the force-induced switch between bleb and pseudopod-driven migration.

Main Methods:

• Utilized a "cell squasher" device to apply controlled uniaxial pressure to chemotaxing *Dictyostelium* cells under soft agarose.
• Monitored changes in cell morphology, motility (blebs vs. pseudopods), actin cytoskeleton organization, and calcium dynamics.
• Investigated the role of extracellular calcium and the Piezo channel using genetic manipulation and calcium imaging.

Main Results:

• As little as 100 Pa of pressure induced a rapid (<10 s) and sustained shift from pseudopod-driven to bleb-driven cell migration.
• Under pressure, cells flattened, lost volume, and reorganized their actin cytoskeleton, with myosin II recruited to the cortex.
• The transition to bleb-driven motility required extracellular calcium and increased cytosolic calcium, and was largely abrogated in cells lacking the Piezo channel.

Conclusions:

• Migrating cells sense mechanical pressure through the Piezo stretch-operated channel.
• Pressure sensing by Piezo mediates calcium influx, which directs the cell migration machinery to favor blebs over pseudopods.
• This mechanotransduction pathway allows cells to adapt their migration strategy in response to mechanical resistance encountered in tissues.