Curved Microfluidic Confinement Reveals Cell-Shape-Dependent Nuclear Mechanotransduction in Adaptive Migration

Area of Science:

• Cell Biology
• Biophysics
• Biomaterials

Background:

• Cells in vivo encounter complex, curved microenvironments formed by the extracellular matrix (ECM) and neighboring cells.
• Existing research on cell migration predominantly examines migration on curved surfaces, with limited understanding of cellular responses to combined confinement and geometric curvature.

Purpose of the Study:

• To investigate cellular adaptive responses to confinement-coupled geometric curvature.
• To explore the mechanisms underlying cell migration in physiologically relevant curved microenvironments.

Main Methods:

• Development of a confined curvature-based microfluidic chip (CCM-Chip) to mimic in vivo physical cues.
• Engineering a microgrooved uniaxial stretching microdevice to manipulate cell shape.
• Analysis of cell shape bending, nuclear deformation, cytoskeletal remodeling, and molecular signaling pathways.

Main Results:

• Cells in the CCM-Chip showed shape bending, nuclear deformation, and cytoskeletal remodeling correlated with local geometric curvature.
• Curvature-induced cell shape changes led to nuclear envelope stretching, initiating downstream nuclear responses.
• Nuclear envelope stretching triggered cPLA2 recruitment to the nucleus, mediated by nesprin and SUN1, a key step in nuclear mechanotransduction.
• Activated cPLA2 promoted stress fiber polarization and enhanced cellular contractility, facilitating curvature-driven cell migration.

Conclusions:

• The study introduces a versatile biomimetic microdevice for studying cell migration.
• Nuclear deformation-induced cPLA2 signaling plays a crucial role in adaptive cell migration in curved environments.
• Findings offer insights into therapeutic strategies targeting cancer metastasis.