MSC−sEV Treatment Polarizes Pro−Fibrotic M2 Macrophages without Exacerbating Liver Fibrosis in NASH

• Main Authors: Lai, R.C (Author), Lam, K.P (Author), Lim, S.K (Author), Sim, W.K (Author), Zhang, B. (Author)
• Format: Article
• Language: English
• Published: MDPI 2023
• Subjects: fibrosis; immunomodulation; M2 macrophage; mesenchymal stem/stromal cells (MSCs); non−alcoholic steatohepatitis (NASH); small extracellular vesicles (sEVs)
• Online Access: View Fulltext in Publisher; View in Scopus

 Mesenchymal stem/stromal cell small extracellular vesicles (MSC−sEVs) have shown promise in treating a wide range of animal models of various human diseases, which has led to their consideration for clinical translation. However, the possibility of contraindication for MSC−sEV use is an important consideration. One concern is that MSC−sEVs have been shown to induce M2 macrophage polarization, which is known to be pro−fibrotic, potentially indicating contraindication in fibrotic diseases such as liver fibrosis. Despite this concern, previous studies have shown that MSC−sEVs alleviate high−fat diet (HFD)−induced non−alcoholic steatohepatitis (NASH). To assess whether the pro−fibrotic M2 macrophage polarization induced by MSC−sEVs could worsen liver fibrosis, we first verified that our MSC−sEV preparations could promote M2 polarization in vitro prior to their administration in a mouse model of NASH. Our results showed that treatment with MSC−sEVs reduced or had comparable NAFLD Activity Scores and liver fibrosis compared to vehicle− and Telmisartan−treated animals, respectively. Although CD163+ M2 macrophages were increased in the liver, and serum IL−6 levels were reduced in MSC−sEV treated animals, our data suggests that MSC−sEV treatment was efficacious in reducing liver fibrosis in a mouse model of NASH despite an increase in pro−fibrotic M2 macrophage polarization. © 2023 by the authors.