Abstract
Background There are no approved drug treatments for liver fibrosis and nonalcoholic steatohepatitis (NASH), an advanced stage of fibrosis which has rapidly become a major cause of cirrhosis. Therefore, development of anti-inflammatory and antifibrotic therapies is desired. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We herein investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. Methods NASH was induced by a 4-week high-fat diet (HFD), and liver fibrosis was induced by intraperitoneal injection of 2 mL/kg 50% carbon tetrachloride (CCl4) twice a week for six weeks. AMSC-EVs were intravenously injected at weeks 3 and 4 in rats with NASH (15 μg/kg) and at week 3 in rats with liver fibrosis (20 μg/kg). The extent of inflammation and fibrosis was evaluated with quantitative reverse transcription polymerase chain reaction and immunohistochemistry. The effect of AMSC-EVs on inflammatory and fibrogenic response was investigated in vitro. Results AMSC-EVs significantly decreased the number of Kupffer cells (KCs) in the liver of rats with NASH and the mRNA expression levels of inflammatory cytokines such as tumor necrosis factor- (Tnf-) α, interleukin- (Il-) 1β and Il-6, and transforming growth factor- (Tgf-) β. Furthermore, AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. In vitro, AMSC-EVs significantly inhibited KC and HSC activation and suppressed the lipopolysaccharide (LPS)/toll-like receptor 4 (TLR4) signaling pathway. Conclusions AMSC-EVs ameliorated inflammation and fibrogenesis in a rat model of NASH and liver fibrosis, potentially by attenuating HSC and KC activation. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease.
Highlights
Chronic tissue injury leads to sustained scarring response that gradually disrupts normal cellular function, eventually leading to failure in multiple epithelial organs such as the lung, kidney, and liver [1]
We previously demonstrated that systemic administration of amnion-derived Mesenchymal stem cells (MSCs) (AMSCs) in rats led to the improvement of severe colitis [10, 11], radiation proctitis [12], pancreatitis [13], and liver fibrosis [14], potentially through secretory factors released from transplanted Amnion-derived mesenchymal stem cell (AMSC)
We evaluated the role of AMSC-Extracellular vesicles (EVs) in a rat model of nonalcoholic steatohepatitis (NASH)
Summary
Chronic tissue injury leads to sustained scarring response that gradually disrupts normal cellular function, eventually leading to failure in multiple epithelial organs such as the lung, kidney, and liver [1]. We previously demonstrated that systemic administration of amnion-derived MSCs (AMSCs) in rats led to the improvement of severe colitis [10, 11], radiation proctitis [12], pancreatitis [13], and liver fibrosis [14], potentially through secretory factors released from transplanted AMSCs. Previous studies showed that MSCs can achieve therapeutic effect via paracrine action and direct differentiation in vivo [15, 16]. Mesenchymal stem cell- (MSC-) based therapy, which has been extensively investigated in regenerative medicine for various organs, can reportedly achieve therapeutic effect in NASH via paracrine action. Extracellular vesicles (EVs) encompass a variety of vesicles released by cells that fulfill functions similar to those of MSCs. We investigated the therapeutic effects of EVs from amnion-derived MSCs (AMSCs) in rats with NASH and liver fibrosis. AMSC-EVs significantly decreased fiber accumulation, KC number, and hepatic stellate cell (HSC) activation in rats with liver fibrosis. AMSC-EV administration should be considered as a new therapeutic strategy for chronic liver disease
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