Exploring the cytoprotective role of mesenchymal stem Cell-Derived exosomes in chronic liver Fibrosis: Insights into the Nrf2/Keap1/p62 signaling pathway

Abstract

Hepatic fibrosis is a common pathology present in most chronic liver diseases. Autophagy is a lysosome-mediated intracellular catabolic and recycling process that plays an essential role in maintaining normal hepatic functions. Nuclear factor erythroid 2-like 2 (Nrf2) is a transcription factor responsible for the regulation of cellular anti-oxidative stress response. This study was designed to assess the cytoprotective effect of mesenchymal stem cell-derived exosomes (MSC-exos) on endothelial-mesenchymal transition (EMT) in Carbon Tetrachloride (CCL₄) induced liver fibrosis. Rats were treated with 0.1 ml of CCL₄ twice weekly for 8 weeks, followed by administration of a single dose of MSC-exos. Rats were then sacrificed after 4 weeks, and liver samples were collected for gene expression analyses, Western blot, histological studies, immunohistochemistry, and transmission electron microscopy. Our results showed that MSC-exos administration decreased collagen deposition, apoptosis, and inflammation. Exosomes modulate the Nrf2/Keap1/p62 pathway, restoring autophagy and Nrf2 levels through modulation of the non-canonical pathway of Nrf2/Keap1/p62. Additionally, MSC-exos regulated miR-153-3p, miR-27a, miR-144 and miRNA-34a expression. In conclusion, the present study shed light on MSC-exos as a cytoprotective agent against EMT and tumorigenesis in chronic liver inflammation.

Keywords: Autophagy; Chronic liver inflammation; Endothelial mesenchymal transition; Liver fibrosis; MSC-derived exosomes; Nrf2/Keap1/p62.