Exosomes derived from human adipose mesenchymal stem cells ameliorate hepatic fibrosis by inhibiting PI3K/Akt/mTOR pathway and remodeling choline metabolism

Abstract

Liver fibrosis is a chronic liver disease with the presence of progressive wound healing response caused by liver injury. Currently, there are no approved therapies for liver fibrosis. Exosomes derived from human adipose mesenchymal stem cells (hADMSCs-Exo) have displayed a prominent therapeutic effect on liver diseases. However, few studies have evaluated therapeutic effect of hADMSCs-Exo in liver fibrosis and cirrhosis, and its precise mechanisms of action remain unclear. Herein, we investigated anti-fibrotic efficacy of hADMSCs-Exo in vitro and in vivo, and identified important metabolic changes and the detailed mechanism through transcriptomic and metabolomic profiling. We found hADMSCs-Exo could inhibit the proliferation of activated hepatic stellate cells through aggravating apoptosis and arresting G1 phase, effectively inhibiting the expression of profibrogenic proteins and epithelial-to-mesenchymal transition (EMT) in vitro. Moreover, it could significantly block collagen deposition and EMT process, improve liver function and reduce liver inflammation in liver cirrhosis mice model. The omics analysis revealed that the key mechanism of hADMSCs-Exo anti-hepatic fibrosis was the inhibition of PI3K/AKT/mTOR signaling pathway and affecting the changes of metabolites in lipid metabolism, and mainly regulating choline metabolism. CHPT1 activated by hADMSCs-Exo facilitated formation and maintenance of vesicular membranes. Thus, our study indicates that hADMSCs-Exo can attenuate hepatic stellate cell activation and suppress the progression of liver fibrosis, which holds the significant potential of hADMSCs-Exo for use as extracellular nanovesicles-based therapeutics in the treatment of liver fibrosis and possibly other intractable chronic liver diseases. Graphical Abstract

Native and engineered extracellular vesicles: novel tools for treating liver disease

“…40 Additionally, hADMSC-EXOs attenuated HSC activation and inhibited the progression of liver fibrosis by inhibiting the PI3K/AKT/mTOR signaling pathway and regulating choline metabolism. 19 AD-MSC-derived exosomes have also been demonstrated to promote the anti-tumour response of NKT cells in rats, resulting in HCC suppression, an increased early apparent diffusion coefficient (ADC), and low-grade tumour differentiation. 41 However, MSC-EVs can also contribute to cancer progression.…”

“…[15][16][17] Furthermore, intravenously injected EVs tend to accumulate in the liver. 18,19 In addition, with the rise of RNA therapy, EVs, as endogenous biological carriers, can protect nucleic acid molecules from being broken down and deliver drugs to the lesion site. Moreover, engineered EVs have recently emerged as a new therapeutic strategy and are promising as an alternative approach to EV-based therapy (Fig.…”

Exosome-Mediated Antigen Delivery: Unveiling Novel Strategies in Viral Infection Control and Vaccine Design

“…Among other examples of phenotypic changes induced, exosomes were shown to contribute to the polarization of macrophages [ 115 ]. Exosomes have also been described as players in epithelial–mesenchymal transition (EMT) in a variety of pathological conditions, including fibrosis and cancer [ 116 , 117 ]. However, the miRNA content of exosomes, depending on the emitting cells, would mediate potentially antagonistic effects on EMT, revealing both the promotion and inhibition roles [ 118 , 119 ].…”

Immunomodulatory Role of Mesenchymal Stem Cells in Liver Transplantation: Status and Prospects

“…This would be promising in treating liver fibrosis, liver injury, cirrhosis, liver failure, and liver cancer. Two recent studies have shown that MSCs could hinder liver fibrosis progression in mice by inhibiting the activation of hepatic stellate cells [20, 21]. Meanwhile, splenic vein injection of MSCs contributed to the attenuation of acute liver injury in dogs [22].…”