Engineered Mesenchymal Stem Cell-Derived Small Extracellular Vesicles Mitigate Liver Fibrosis by Delivering USP10 to...

Area of Science:

• Cell Biology
• Regenerative Medicine
• Hepatology

Background:

• Mesenchymal stem cells (MSCs) show therapeutic potential for liver fibrosis.
• The paracrine mechanisms of MSCs, especially small extracellular vesicles (sEVs), are under investigation.
• Understanding these mechanisms is crucial for developing effective fibrosis treatments.

Purpose of the Study:

• To investigate the anti-fibrotic effects of MSC-derived sEVs (MSCs-sEVs) in liver fibrosis.
• To elucidate the underlying signaling pathways involved in MSCs-sEVs-mediated liver repair.
• To identify key molecules within MSCs-sEVs responsible for their therapeutic action.

Main Methods:

• Carbon tetrachloride (CCL4)-induced liver fibrosis model in mice.
• In vivo and in vitro experiments assessing macrophage phenotype modulation.
• Mass spectrometry to identify proteins enriched in MSCs-sEVs.
• Genetic engineering to enhance USP10 content in MSCs-sEVs.

Main Results:

• MSCs and their derived sEVs significantly ameliorated liver inflammation and fibrosis.
• MSCs-sEVs induced an anti-fibrotic phenotype in liver macrophages.
• Ubiquitin-specific peptidase 10 (USP10) was identified as a key protein in MSCs-sEVs, stabilizing Krüppel-like factor 4 (KLF4).
• USP10-KLF4 axis modulated macrophage phenotype via NF-κB/STAT6 signaling and MMP12 transcription.
• Enhanced USP10 in MSCs-sEVs potentiated anti-fibrotic effects.

Conclusions:

• MSCs-sEVs are major mediators of MSCs' anti-fibrotic effects.
• The USP10-KLF4 pathway in macrophages is critical for MSCs-sEVs' therapeutic action.
• MSCs-sEVs represent a promising cell-free therapeutic strategy for liver fibrosis.