Mesenchymal stem cells differentiate dynamic from static load through variable regulation of the Hippo pathway

Area of Science:

• Cell biology
• Mechanobiology
• Biophysics

Background:

• Cellular mechanical environment significantly impacts cell behavior.
• Dynamic loading often promotes anabolic responses, while static loading can lead to catabolic pathophysiology.
• The mechanisms by which cells differentiate between static and dynamic mechanical stimuli remain unclear.

Purpose of the Study:

• To investigate how mesenchymal stem cells (MSCs) differentiate between static strain (SS) and dynamic strain (DS).
• To elucidate the role of the Hippo signaling pathway and actin remodeling in MSCs' response to mechanical loading.
• To understand the molecular mechanisms underlying YAP localization in response to different loading conditions.

Main Methods:

• Applying static and dynamic mechanical strain to MSCs.
• Analyzing nuclear YAP localization using immunofluorescence.
• Investigating Hippo pathway signaling through enzyme phosphorylation.
• Examining actin cytoskeleton remodeling via microscopy.
• Utilizing genetic manipulation (LATS1/2 inhibition, AMOT knockdown).

Main Results:

• Static strain (SS) increased nuclear YAP localization, mediated by PP2Ac association with nuclear MST1/2.
• Dynamic strain (DS) did not increase nuclear YAP but activated Hippo signaling via MST1/2 and YAP phosphorylation.
• DS induced actin remodeling with thicker, aligned fibers; SS reinforced existing actin networks.
• DS-induced actin remodeling involved LATS1/2 and AMOT phosphorylation, affecting AMOT binding.
• SS-induced actin reinforcement sequestered AMOT, influencing YAP dephosphorylation.

Conclusions:

• MSCs possess mechanisms to differentiate between static and dynamic mechanical loading.
• The Hippo pathway and actin cytoskeleton play differential roles in responding to SS and DS.
• Actin remodeling and AMOT dynamics are critical mediators in MSCs' response to mechanical cues.
• These findings reveal nuanced mechanical effects on the Hippo pathway in MSCs.