Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis
Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver failure globally and is characterized by hepatic steatosis and inflammation, which may progress to fibrosis, the severity of which is highly predictive of patient demise and death. In view of the lack o...
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2025-01-01
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| author | Xinlei Li Ruju Chen Sherri Kemper Zhaohui Xu David R. Brigstock |
| author_facet | Xinlei Li Ruju Chen Sherri Kemper Zhaohui Xu David R. Brigstock |
| author_sort | Xinlei Li |
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| description | Introduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver failure globally and is characterized by hepatic steatosis and inflammation, which may progress to fibrosis, the severity of which is highly predictive of patient demise and death. In view of the lack of treatment options for MASH, we investigated the therapeutic properties of extracellular vesicles (EVs) from normal human hepatocytes, which we have previously been shown to alleviate toxin-mediated hepatic fibrosis in mice. Methods: C57BI/6J mice were fed a choline-deficient amino acid-defined high (60%) fat (CDAA-HF) diet for up to 12 weeks while receiving i.p. administration of EVs purified from cultured human HepG2 hepatocytes. Results: CDAA-HF diet consumption resulted in severe hepatic steatosis, increased frequency of CD45+ lymphocytes and F4/80+ macrophages, robust production of aortic smooth muscle actin (ACTA2), and deposition of interstitial collagen, as well as altered serum levels of ALT, AST, cholesterol, triglycerides, alkaline phosphatase, unconjugated bilirubin, and total protein, thus recapitulating typical MASH phenotypes. EVs administered preventively or therapeutically resulted in the restoration of serum marker levels, reduced hepatic inflammation and attenuation of collagen deposition, ACTA2 production, and expression of fibrosis-associated genes. HepG2 EVs contained 205 miRs and, among the 30 most abundant miRs, seven (miRs-423-5p, -483-5p, -191-5p, -148a-3p, -423-3p, -92a-3p, -122-5p) are predicted to directly target fibrosis-related genes (<i>collagen</i>s, <i>ACTA2</i>, <i>MMP</i>s, and <i>TIMP</i>s). Conclusions: Hepatocyte EVs are therapeutic in a mouse model of diet-induced steatohepatitis with fibrosis. Further studies of hepatocyte EVs or their cargo components as novel therapeutics for MASH in humans are warranted, including treatment of fibrotic stages, which are associated with clinical demise and are predictive of patient death. |
| format | Article |
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| institution | DOAJ |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-77bf4bce1557464aa2b5216d5ef4c53c2025-08-20T02:44:34ZengMDPI AGBiomedicines2227-90592025-01-0113227410.3390/biomedicines13020274Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with FibrosisXinlei Li0Ruju Chen1Sherri Kemper2Zhaohui Xu3David R. Brigstock4Center for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USACenter for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USADepartment of Infectious Diseases, St. Jude Children’s Research Hospital, Memphis, TN 38105, USACenter for Clinical and Translational Research, The Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH 43205, USAIntroduction: Metabolic dysfunction-associated steatohepatitis (MASH) is a leading cause of liver failure globally and is characterized by hepatic steatosis and inflammation, which may progress to fibrosis, the severity of which is highly predictive of patient demise and death. In view of the lack of treatment options for MASH, we investigated the therapeutic properties of extracellular vesicles (EVs) from normal human hepatocytes, which we have previously been shown to alleviate toxin-mediated hepatic fibrosis in mice. Methods: C57BI/6J mice were fed a choline-deficient amino acid-defined high (60%) fat (CDAA-HF) diet for up to 12 weeks while receiving i.p. administration of EVs purified from cultured human HepG2 hepatocytes. Results: CDAA-HF diet consumption resulted in severe hepatic steatosis, increased frequency of CD45+ lymphocytes and F4/80+ macrophages, robust production of aortic smooth muscle actin (ACTA2), and deposition of interstitial collagen, as well as altered serum levels of ALT, AST, cholesterol, triglycerides, alkaline phosphatase, unconjugated bilirubin, and total protein, thus recapitulating typical MASH phenotypes. EVs administered preventively or therapeutically resulted in the restoration of serum marker levels, reduced hepatic inflammation and attenuation of collagen deposition, ACTA2 production, and expression of fibrosis-associated genes. HepG2 EVs contained 205 miRs and, among the 30 most abundant miRs, seven (miRs-423-5p, -483-5p, -191-5p, -148a-3p, -423-3p, -92a-3p, -122-5p) are predicted to directly target fibrosis-related genes (<i>collagen</i>s, <i>ACTA2</i>, <i>MMP</i>s, and <i>TIMP</i>s). Conclusions: Hepatocyte EVs are therapeutic in a mouse model of diet-induced steatohepatitis with fibrosis. Further studies of hepatocyte EVs or their cargo components as novel therapeutics for MASH in humans are warranted, including treatment of fibrotic stages, which are associated with clinical demise and are predictive of patient death.https://www.mdpi.com/2227-9059/13/2/274MASLDMASHextracellular vesicleexosomehepatocyteliver |
| spellingShingle | Xinlei Li Ruju Chen Sherri Kemper Zhaohui Xu David R. Brigstock Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis Biomedicines MASLD MASH extracellular vesicle exosome hepatocyte liver |
| title | Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis |
| title_full | Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis |
| title_fullStr | Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis |
| title_full_unstemmed | Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis |
| title_short | Therapeutic Actions of Hepatocyte Extracellular Vesicles in a Murine Model of Diet-Induced Steatohepatitis with Fibrosis |
| title_sort | therapeutic actions of hepatocyte extracellular vesicles in a murine model of diet induced steatohepatitis with fibrosis |
| topic | MASLD MASH extracellular vesicle exosome hepatocyte liver |
| url | https://www.mdpi.com/2227-9059/13/2/274 |
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