Engineered Nestin⁺ TSPC-Derived Exosomes Promote Tendon Repair Via Metabolic Reprogramming

Area of Science:

• Regenerative Medicine
• Cell Biology
• Biochemistry

Background:

• Tendon repair is a significant clinical challenge with few effective treatments.
• Nestin-positive tendon stem/progenitor cells (TSPCs) are crucial for tendon healing but face clinical translation hurdles.

Purpose of the Study:

• To investigate the therapeutic potential of exosomes derived from engineered Nestin-overexpressing TSPCs (Nes-EVs) for tendinopathy.
• To elucidate the underlying mechanisms by which Nes-EVs promote tendon healing.

Main Methods:

• Lentiviral Nestin overexpression in TSPCs to generate Nes-EVs.
• In vitro assessment of Nes-EVs' effects on cellular senescence and tenogenic differentiation.
• In vivo evaluation of Nes-EVs in collagenase-induced and aged murine tendinopathy models.
• Integrated transcriptomic and metabolomic profiling of TSPCs and Nes-EVs.

Main Results:

• Nes-EVs significantly improved motor function, tissue architecture, and collagen homeostasis in tendinopathy models.
• Nes-EVs reduced senescence markers and promoted tenogenic differentiation in vitro.
• Transcriptomic and metabolomic analyses revealed enrichment in pantothenate and CoA biosynthesis.
• Nes-EVs enhanced tenocyte mitochondrial function, boosting ATP production and reducing oxidative stress.

Conclusions:

• Nes-EVs represent a promising acellular therapeutic strategy for tendinopathy.
• Nes-EVs coordinate tendon metabolism and homeostasis, offering a novel treatment approach.
• Targeting cellular metabolism via Nes-EVs revitalizes damaged tendons.