Abstract
BackgroundEffective treatments for acute-on-chronic liver failure (ACLF) are lacking. Human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) have been applied in tissue regeneration and repair, acting through paracrine effects, cell fusion, and actual transdifferentiation. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models.MethodsWistar rats aged 6 weeks were intraperitoneally administered porcine serum (PS) at a dose of 0.5 mL twice per week for 11 weeks to generate an immune liver fibrosis model. After 11 weeks, rats with immune liver fibrosis were injected intravenously with lipopolysaccharide (LPS) to induce an ACLI model or combined LPS and D-galactosamine (D-GalN) to induce an ACLF model. The rats with ACLI or ACLF were injected intravenously with 2×106 hUC-MSCs, 4×106 hUC-MSCs, or 0.9% sodium chloride as a control. The rats were sacrificed at 1, 2, 4, and 6 weeks (ACLI rats) or 4, 12, and 24 h (ACLF rats). The blood and liver tissues were collected for biochemical and histological investigation.ResultsThe application of hUC-MSCs in rats with ACLI and ACLF led to a significant decrease in the serum levels of ALT, AST, TBil, DBil, ALP, ammonia, and PT, with ALB gradually returned to normal levels. Inflammatory cell infiltration and collagen fiber deposition in liver tissues were significantly attenuated in ACLI rats that received hUC-MSCs. Inflammatory cell infiltration and apoptosis in liver tissues of ACLF rats that received hUC-MSCs were significantly attenuated. Compared with those in the rats that received 0.9% sodium chloride, a significant reduction in proinflammatory cytokine levels and elevated serum levels of hepatocyte growth factor (HGF) were found in ACLF rats that received hUC-MSCs. Furthermore, Notch, IFN-γ/Stat1, and IL-6/Stat3 signaling were inhibited in ACLI/ACLF rats that received hUC-MSCs.ConclusionshUC-MSC transplantation can improve liver function, the degree of fibrosis, and liver damage and promote liver repair in rats with ACLI or ACLF, mediated most likely by inhibiting Notch signaling and reversing the imbalance of the Stat1/Stat3 pathway.
Highlights
Effective treatments for acute-on-chronic liver failure (ACLF) are lacking
The application of hUC-Mesenchymal stem cells (MSCs) in rats with acute-on-chronic liver injury (ACLI) and ACLF led to a significant decrease in the serum levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST), TBil, DBil, alkaline phosphatase (ALP), ammonia, and prothrombin time (PT), with ALB gradually returned to normal levels
The serum ALB level in rats receiving 4×106 Human umbilical cord-derived mesenchymal stem cells (hUCMSCs) returned to normal levels, but serum ALT, AST, and TBil levels and other indicators did not return to normal levels after hUC-MSC treatment for 6 weeks (Fig. 2a–f)
Summary
Effective treatments for acute-on-chronic liver failure (ACLF) are lacking. The present study was designed to investigate the therapeutic potential of hUC-MSCs in acute-on-chronic liver injury (ACLI) and ACLF rat models. Chronic liver disease (CLD) refers to a type of disease with a history of cirrhosis or noncirrhosis of the liver for more than 6 months. According to the latest global disease burden research data, 1.5 billion people worldwide suffered from CLD in 2017, the most common types of which are nonalcoholic fatty liver disease (NAFLD), viral hepatitis, and alcoholic liver disease [1]. ACLI is a common disease in the clinic, but the disease progresses rapidly in some patients and develops into acute-on-chronic liver failure (ACLF). Artificial liver treatment plays an important role, but its clinical application is limited due to the shortage of blood supplies, infections, bleeding, and other complications [4, 5].
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