Energy deficiency selects crowded live epithelial cells for extrusion

Area of Science:

• Cell Biology
• Physiology
• Biophysics

Background:

• Epithelial cells form a protective barrier through rapid cell division and death.
• Imbalances in cell division and death can lead to barrier dysfunction or tumor formation.
• Mechanical forces, mediated by Piezo1, influence cell division and crowding-induced cell extrusion.

Purpose of the Study:

• To identify the specific mechanisms that select which crowded cell undergoes extrusion.
• To elucidate the role of cellular energy and membrane potential in this selection process.
• To understand the upstream regulators of Piezo1 in epithelial cell turnover.

Main Methods:

• Investigated cellular responses to crowding in epithelial cells.
• Measured cellular energy (ATP levels) and membrane potential.
• Analyzed ion channel activity, including epithelial sodium channels (ENaC), K_v1.1, K_v1.2, and SWELL1.
• Observed water transport and cell volume changes.

Main Results:

• Crowded cells with the lowest energy and membrane potential are preferentially selected for extrusion.
• Crowding induces sodium entry via ENaC, leading to cell depolarization.
• Cells with limited ATP cannot repolarize and undergo water egress, causing shrinkage and activating extrusion.
• This mechanism acts upstream of Piezo1, involving ENaC as a tension sensor.

Conclusions:

• Cellular energy levels and membrane potential are critical determinants of cell extrusion.
• ENaC acts as a sensor, identifying low-energy cells for extrusion and preventing inappropriate activation of Piezo1.
• Water regulation and specific ion channels are key regulators of epithelial cell turnover and barrier integrity.