Abstract
BackgroundCholestatic liver injury can lead to serious symptoms and prognoses in the clinic. Currently, an effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury.MethodsThe treatment effect of MenSCs on chronic cholestatic liver injury was verified in 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC)-induced C57/BL6 mice. Pathological, fibrosis area in the liver tissue and serum liver enzymes were tested. Proteomics and western blot were used to explore the related targets and molecular mechanisms. Adeno-associated virus (AAV) 9-infected mice were applied for verification.ResultsMenSCs markedly improved the survival rate of the DDC-treated mice (60% vs. 100%), and decreased the mouse serum aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L, p < 0.001), alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L, p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L, p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 μmol/L, p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 μmol/L, p < 0.0001) levels as well as intrahepatic cholestasis, bile duct dilation and fibrotic areas (16.12 vs. 6.57%, p < 0.05). The results further indicated that MenSCs repaired the DDC-induced liver tight junction (TJ) pathway and bile transporter (OATP2, BSEP and NTCP1) injury, thereby inhibiting COL1A1, α-SMA and TGF-β1 activation by upregulating liver β-catenin expression.ConclusionsMenSC transplantation could be an effective treatment method for cholestatic liver injury in mice. MenSCs may exhibit therapeutic effects by regulating β-catenin expression.
Highlights
Cholestatic liver injury can lead to serious symptoms and prognoses in the clinic
The results showed positive expression of CD29, CD73, CD90 and CD105 and negative expression of CD34, CD45, CD117 and human leukocyte antigen-DR (HLA-DR) (Fig. 1A)
The results showed that menstrual blood-derived stem cells (MenSCs) could significantly reduce the levels of Aspartate aminotransferase (AST) (169.4 vs. 108.0 U/L, p < 0.001), Alanine aminotransferase (ALT) (279.0 vs. 228.9 U/L, p < 0.01), alkaline phosphatase (ALP) (45.6 vs. 10.6 U/L, p < 0.0001), direct bilirubin (DBIL) (108.3 vs. 14.0 μmol/L, p < 0.0001) and total bilirubin (TBIL) (179.2 vs. 43.3 μmol/L, p < 0.0001), indicating that MenSC transplantation could restore DDC-induced mouse liver damage and liver damage-induced jaundice (Fig. 2E)
Summary
Cholestatic liver injury can lead to serious symptoms and prognoses in the clinic. An effective medical treatment is not available for cholestatic liver injury. Human menstrual blood-derived stem cells (MenSCs) are considered as an emerging treatment in various diseases. This study aimed to explore the treatment effect of MenSCs in cholestatic liver injury. Cholestatic liver injury is a rare chronic liver disease characterized by the disruption of bile acid (BA) flow and increased BA concentration in the systemic circulation. Cholestatic liver injury mainly includes primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) [1, 2]. Excessive accumulation of bile components, including bile acid, cholesterol and bilirubin, in hepatic and systemic circulation is considered the major driver of liver injury. Adults with different phenotypes of cholestasis have increasingly been evaluated for variants in these genes to identify specific cholestasis-related genes [8, 9]
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