Dimensionality and spreading influence MSC YAP/TAZ signaling in hydrogel environments

Area of Science:

• Biomaterials Science
• Cell Biology
• Tissue Engineering

Background:

• Understanding cellular responses to microenvironmental signals is crucial for developing effective biomaterial therapies.
• Yeast and TAZ (YAP/TAZ) proteins are central mediators of mechanosensitive signaling pathways.
• The regulation of YAP/TAZ by combined factors like stiffness, degradability, and culture dimensionality remains incompletely understood.

Purpose of the Study:

• To investigate how hydrogel stiffness and degradability, in conjunction with culture dimensionality, influence YAP/TAZ signaling in human mesenchymal stem cells (MSCs).
• To elucidate the interplay between microenvironmental cues and cell-biomaterial interactions in regulating mechanotransduction.

Main Methods:

• Utilized covalently crosslinked norbornene-functionalized hyaluronic acid (HA) hydrogels with tunable stiffness and degradability.
• Investigated MSCs cultured on 2D surfaces versus encapsulated within 3D hydrogels.
• Assessed cell spreading and YAP/TAZ nuclear localization using microscopy and confirmed findings with pharmacological inhibition of YAP/TAZ and actin polymerization.

Main Results:

• MSCs showed increased spreading and YAP/TAZ nuclear localization on stiffer hydrogels in 2D cultures.
• Conversely, MSCs encapsulated in degradable hydrogels exhibited the opposite trend.
• In stiffness-matched, less degradable hydrogels, YAP/TAZ nuclear translocation was enhanced in spread cells, confirming the interplay of factors.

Conclusions:

• YAP/TAZ signaling is demonstrably responsive to both hydrogel stiffness and degradability.
• The dimensionality of cell-biomaterial interactions significantly modulates the cellular response to these microenvironmental signals.
• These findings provide fundamental insights into mechanotransduction for advanced biomaterial design.