Substrate stiffness and cellular microenvironment regulate cell and junction mechanics in iPSC-derived brain...

Area of Science:

• Neuroscience
• Biophysics
• Cell Biology

Background:

• The blood-brain barrier (BBB) is crucial for central nervous system protection.
• Brain tissue stiffness changes with development, aging, and disease, affecting BBB integrity.
• Mechanisms of endothelial cell adaptation to mechanical cues are poorly understood.

Purpose of the Study:

• To investigate how brain endothelial cells sense and adapt to varying substrate stiffness.
• To explore the role of astrocytes and pericytes in modulating endothelial mechanics.
• To understand how cancer cells disrupt BBB mechanics and integrity.

Main Methods:

• Utilized human induced pluripotent stem cell-derived brain microvascular endothelial cells (iBMECs).
• Employed atomic force microscopy to quantify Young's modulus at cellular regions.
• Investigated responses to a range of substrate stiffness (1-194 kPa) and co-culture conditions.

Main Results:

• iBMECs displayed mechanical polarization on soft substrates, with higher stiffness at tricellular junctions.
• Supraphysiological stiffness eliminated regional stiffness differences and reduced overall cell stiffness.
• Astrocytes and pericytes reduced global stiffness but maintained tricellular reinforcement.
• Cancer cells abolished junction polarization and suppressed stiffness, especially on soft substrates.

Conclusions:

• BBB endothelial cell mechanics are spatiotemporally regulated by matrix stiffness and cellular context.
• Mechanical cues and cell interactions critically influence BBB structure and function.
• Findings offer insights into BBB disruption in neurological diseases and metastasis.