Substrate mechanics controls adipogenesis through YAP phosphorylation by dictating cell spreading

Area of Science:

• Biomedical Engineering
• Stem Cell Biology
• Mechanobiology

Background:

• Mesenchymal stem cells (MSCs) are crucial for regenerative medicine, but their differentiation into fat (adipogenesis) or bone (osteogenesis) must be controlled.
• The mechanosensitive proteins YAP/TAZ play a key role in MSC fate decisions, influenced by the mechanical properties of their environment.
• Understanding how mechanical forces regulate YAP/TAZ is vital for directing MSC differentiation and preventing unwanted adipogenesis.

Purpose of the Study:

• To investigate the precise mechanisms by which substrate mechanics influence MSC adipogenesis through YAP/TAZ regulation.
• To develop bioengineering tools to differentiate mechanical from biological stimuli in MSC fate determination.
• To explore the therapeutic potential of mechanically regulating YAP/TAZ for applications like tumor treatment.

Main Methods:

• Utilized novel bioengineering tools to isolate mechanical effects on MSCs.
• Investigated the role of cell spreading and substrate dimensionality in YAP/TAZ regulation.
• Analyzed YAP phosphorylation as a key mediator of mechanical repression.
• Assessed the sufficiency of YAP repression for inducing adipogenesis under various conditions.

Main Results:

• Mechanical repression of YAP in MSCs is mediated by phosphorylation and is dependent on cell spreading, which is influenced by substrate dimensionality.
• YAP repression alone is sufficient to induce MSC adipogenesis, irrespective of the biological environment, TEAD nuclear localization, or focal adhesion status.
• Demonstrated a practical application of YAP mechanical regulation for inducing adipogenic transdifferentiation in tumor contexts.

Conclusions:

• Substrate mechanics directly impact MSC fate by regulating YAP/TAZ activity, primarily through phosphorylation-dependent YAP repression.
• Cell spreading, downstream of substrate mechanics and dimensionality, is the critical factor in this mechanical repression.
• Harnessing the mechanical regulation of YAP offers a novel strategy for controlling MSC differentiation and has potential therapeutic implications, including in cancer therapy.