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

• Published in: Journal of nanobiotechnology 2023-01, Vol.21 (1), p.29-29, Article 29
• Main Authors: Zhang, Zilong, Shang, Jin, Yang, Qinyan, Dai, Zonglin, Liang, Yuxin, Lai, Chunyou, Feng, Tianhang, Zhong, Deyuan, Zou, Haibo, Sun, Lelin, Su, Yuhao, Yan, Su, Chen, Jie, Yao, Yutong, Shi, Ying, Huang, Xiaolun
• Format: Article
• Language: English
• Subjects: 1-Phosphatidylinositol 3-kinase; AKT protein; Animals; Antibodies; Apoptosis; Body fat; Care and treatment; Cell activation; Cell cycle; Cell organelles; Cell proliferation; Cellular signal transduction; Choline; Choline - metabolism; Cirrhosis; Collagen; Exosomes; Exosomes - metabolism; Fibrosis; G1 phase; Health aspects; Homeopathy; Human adipose mesenchymal stem cells; Humans; In vivo methods and tests; Lipid metabolism; Lipids; Liposuction; Liver; Liver cirrhosis; Liver Cirrhosis - metabolism; Liver Cirrhosis - therapy; Liver diseases; Liver fibrosis; Materia medica and therapeutics; Medical research; Medicine, Experimental; Mesenchymal Stem Cells; Metabolic regulation; Metabolism; Metabolites; Metabolomics; Mice; Nanomedicine; Nanoparticles; Phosphatidylinositol 3-Kinases - metabolism; Physiological aspects; Protein kinases; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Signal transduction; Stellate cells; Stem cell transplantation; Stem cells; Therapeutics; Therapeutics, Experimental; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcriptomics; Transplantation; Transplants & implants; Wound healing
• ISSN: 1477-3155; 1477-3155
• DOI: 10.1186/s12951-023-01788-4

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.