Unraveling the Exosome-miR-133a Axis: Targeting TGF-β Signaling via WJ-MSC-Derived Exosomes for Anti-Fibrotic Therapy in Liver Fibrosis

Authors
Sahar Saki
Sajad Monjezi
Fatemeh Ghaffari
Ghazal Orak
Samaneh Salehipour Bavarsad
Azam Khedri
Mahdi Hatami
Cellular and Molecular Research Center, Medical Basic Sciences Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
10.61186/ibj.4357
Abstract
Background: One of the primary drivers of liver fibrosis is the excessive accumulation of extracellular matrix (ECM), primarily caused by the over-proliferation of hepatic star-shaped cells (HSCs). The activation of HSCs by transforming growth factor beta (TGF-β) has a critical role in initiating fibrosis. Recent studies have suggested that miRNA-133a significantly regulates the fibrogenesis process, which its downregulation is associated with the fibrosis progression. Understanding the role of miRNA-133a provides potential therapeutic insights for targeting TGF-β signaling and mitigating liver fibrosis. We investigated whether exosomes could attenuate liver fibrosis by enhancing the antifibrotic effects of miR-133a.

Methods: The LX-2 cell line was treated with TGF-β for 24 hours, followed by an additional 24 hours of treatment with exosomes. After this treatment period, we assessed the mRNA expression levels of α-SMA, collagen 1, and miR-133a, as well as the protein levels of p-Smad3.

Results: TGF-β exposure significantly increased the expression level of α-SMA and collagen 1 genes and elevated the levels of p-Smad3 protein. Additionally, it resulted in a significant downregulation of miR-133a compared to the control group. Exosome administration effectively reduced the TGF-β-induced upregulation of p-Smad3, α-SMA, and collagen 1 genes, but increased miR-133a expression levels.

Conclusion: Our findings indicate that by partially mitigating the downregulation of miR-133a, exosomes can effectively inhibit the persistent activation of HSCs. Furthermore, in the context of in vitro liver fibrosis, exosomes can suppress the TGF-β/Smad3 pathway, reducing the accumulation of ECM.
Keywords
exosomes
Hepatic Stellate Cells
liver fibrosis
MicroRNAs