Abstract
BackgroundExtracellular vesicles (EVs) are recognized as novel cell-free therapeutics. Non-alcoholic steatohepatitis (NASH) remains a critical health problem. Herein, we show that EVs from pan peroxisome proliferator-activated receptor agonist-primed induced mesenchymal stem cell (pan PPAR-iMSC-EVs) has unique cargo protein signatures, and demonstrate its therapeutic function in NASH.ResultsA unique protein signatures were identified in pan PPAR-iMSC-EVs against those from non-stimulated iMSC-EVs. NASH mice receiving pan PPAR-iMSC-EVs showed reduced steatotic changes and ameliorated ER stress and mitochondiral oxidative stress induced by inflammation. Moreover, pan PPAR-iMSC-EVs promoted liver regeneration via inhibiting apoptosis and enhancing proliferation.ConclusionsWe conclude that our strategy for enriching unique cargo proteins in EVs may facilitate the development of novel therapeutic option for NASH.Graphical
Highlights
Extracellular vesicles (EVs) are recognized as novel cell-free therapeutics
Bioinformatic analyses showed that the signature of pan Peroxisome proliferator-activated receptors (PPARs)-stimulated induced Mesenchymal stem cells (MSCs) (iMSCs) was significantly enriched in various pathways, including the PI3K-AKT, cell cycle, PPAR, and apoptosis signaling pathways (Fig. 1D), and the expression patterns were validated using qPCR (Additional file 1: Fig. S2)
Western blot analysis revealed that pan PPAR-iMSC-EVs expressed the typical EV markers CD9 and TSG101 (Fig. 1G), whereas their expression was not observed in pan PPAR-stimulated iMSCs
Summary
Non-alcoholic steatohepatitis (NASH) remains a critical health problem. NAFLD can develop into non-alcoholic steatohepatitis (NASH), an advanced form of fatty liver disease. The hallmarks of NASH include hepatic steatosis and inflammation, along with hepatocyte damage [2, 3]. Several underlying mechanisms, such as endoplasmic reticulum (ER) stress, oxidative stress, and inflammation, are responsible for the pathogenesis of NASH [4,5,6,7]. Characterized by steatosis, inflammation, ER stress, and parenchymal injury, NASH is an advanced and aggressive form of NAFLD which can progress to cirrhosis and hepatocellular cancer [8]. Only a few drugs have shown early efficacy, and lifestyle modification remains the key to alleviating NASH/NAFLD [3]
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