A dynamic matrix potentiates mesenchymal stromal cell paracrine function via an effective mechanical dose

Area of Science:

• Biomaterials Science
• Cell Biology
• Tissue Engineering

Background:

• Mesenchymal stromal cells (MSCs) are crucial for tissue development through their paracrine function, which is influenced by physical factors.
• The extracellular matrix (ECM) surrounding MSCs is dynamic, with stiffness changes being a common remodeling event.
• The effect of dynamic ECM stiffness changes on MSC paracrine function remains largely unexplored.

Purpose of the Study:

• To investigate the influence of dynamic changes in extracellular matrix (ECM) stiffness on the paracrine function of mesenchymal stromal cells (MSCs).
• To determine if varying the timing of ECM stiffening affects MSC paracrine activity and associated signaling pathways.

Main Methods:

• Utilized alginate hydrogels with controlled, time-dependent stiffening to mimic dynamic ECM changes.
• Cultured MSCs within hydrogels of varying stiffness (static soft, static stiff, dynamically stiffening at different time points).
• Assessed MSC paracrine function and quantified Yes-associated protein (YAP) activation, correlating it with F-actin polymerization.

Main Results:

• A stiffer static matrix (14.72 kPa) significantly enhanced MSC paracrine function compared to a soft matrix (2.44 kPa).
• Stiffness-induced potentiation of paracrine function was mediated by YAP activation, triggered by F-actin polymerization.
• Dynamic stiffening on day 3 showed stronger YAP activation than static stiff conditions, while stiffening on day 5 resulted in weaker activation.

Conclusions:

• Increasing mechanical dose levels of the ECM promotes the paracrine function of MSCs.
• An optimal, effective mechanical dose exists that can modulate MSC paracrine function.
• The timing of ECM stiffening critically influences YAP activation and subsequent MSC paracrine signaling.