Membrane Tension Integrates Physical and Signaling Cues to Gate Cell Fate Transitions

Area of Science:

• Cell biology
• Developmental biology
• Biophysics

Background:

• Physical forces, like mechanical stretch, influence cell behavior and fate.
• The alveolar epithelium's development involves FGF signaling and mechanical cues, but their precise roles in AT1 and AT2 cell specification are unclear.

Purpose of the Study:

• To investigate the role of cell membrane tension (CMT) as a regulator of epithelial cell fate in mouse and human lungs.
• To understand how CMT integrates with signaling pathways (FGF, ERK, YAP/TAZ) and physical cues to control AT1 and AT2 cell differentiation.
• To explore the link between CMT, cell differentiation, and the development of lung fibrosis.

Main Methods:

• Analysis of cell membrane tension dynamics during alveolar epithelial differentiation in mouse and human lung models.
• Investigating the impact of altered CMT on signaling pathways, including FGFR2 endocytosis, ERK activation, and YAP/TAZ nuclear translocation.
• Examining the influence of intrinsic factors (β-catenin) and extrinsic cues (fibroblast wrapping, confinement) on CMT and cell fate.
• Characterizing the KRT8⁺ transitional state in relation to fibrosis.

Main Results:

• Cell membrane tension (CMT) drops prior to epithelial cell differentiation and is spatially patterned, dictating AT1 and AT2 cell identity acquisition.
• Reduced CMT enhances FGFR2 endocytosis and ERK signaling, promoting AT2 cell differentiation.
• Lower CMT facilitates architectural remodeling, enabling stretch-mediated YAP/TAZ nuclear entry crucial for AT1 cell maturation.
• Intrinsic β-catenin and extrinsic cues (embedding, osmotic compression, fibroblast wrapping) elevate CMT, restricting differentiation.
• Combined intrinsic and extrinsic tension induce a KRT8⁺ transitional state in alveolar epithelial cells, a phenotype observed in fibrotic lungs.

Conclusions:

• Cell membrane tension is a conserved regulator integrating physical and molecular signals to control lung epithelial cell fate.
• Dynamic changes in CMT are essential for both AT1 and AT2 cell differentiation.
• Aberrant regulation of CMT, through combined intrinsic and extrinsic factors, contributes to a transitional cell state associated with lung fibrosis.