Dynamic Mechanical Loading Reprograms Meniscus Cell-Derived Extracellular Vesicles to Enhance Their Regenerative...

Area of Science:

• Biomaterials Science
• Regenerative Medicine
• Tissue Engineering

Background:

• The meniscus is vital for knee function, but its poor healing capacity presents a significant challenge for regeneration after injury.
• Extracellular vesicles (EVs) show therapeutic potential for tissue repair but face limitations in yield and bioactivity for clinical use.
• Understanding how to enhance EV production and function is crucial for their therapeutic application.

Purpose of the Study:

• To investigate the effects of dynamic mechanical loading on the production, composition, and function of meniscus fibrochondrocyte-derived EVs (MFC-EVs).
• To determine if mechanical stimulation can enhance the regenerative capacity of MFC-EVs for potential therapeutic applications in meniscus repair.

Main Methods:

• Meniscus fibrochondrocytes were cultured and subjected to physiologically relevant cyclic tensile loading using a custom bioreactor.
• EVs were collected, and their production, size, tetraspanin expression, and protein cargo were analyzed.
• The functional effects of mechanically stimulated EVs on recipient mesenchymal stromal cells (MSCs) were assessed by measuring aggrecan expression.

Main Results:

• Mechanical loading significantly increased the production and secretion of MFC-EVs via an ESCRT-independent pathway.
• Mechanically primed EVs enhanced aggrecan expression in MSCs, indicating improved regenerative function.
• Proteomic analysis revealed that loaded EVs were enriched in extracellular matrix, cytoskeleton proteins, and pathways involved in tissue morphogenesis and cartilage development.

Conclusions:

• Physiologic mechanical loading enhances both the yield and regenerative potency of MFC-EVs.
• The enhanced bioactivity of loaded EVs is attributed to an enrichment of specific proteins involved in matrix production and tissue development.
• This study provides a scalable, biologically inspired method for engineering potent EV therapeutics for meniscus repair and broader musculoskeletal regeneration.