Human Umbilical Cord Mesenchymal Stem Cells Ameliorate Hepatic Stellate Cell Activation and Liver Fibrosis by Upregulating MicroRNA-455-3p through Suppression of p21-Activated Kinase-2.

Qing Zhou,Hongda Li,Yuting Kuang,Yong Zhang,Sanrong Xu,Xuemei Zhuansun,Tengfei Gu,Kai-Chiang Yang

doi:10.1155/2021/6685605

Abstract

Mesenchymal stem cells (MSCs) were shown to have potential therapeutic effects for treatment of liver fibrosis, and dysregulated expression of microRNAs (miRNAs) played a pivotal role in the pathogenesis of liver fibrosis by regulating their downstream target genes. However, the mechanism by which MSCs affect the progression of liver fibrosis by regulating miRNA expression remains unclear. Here, we investigated whether human umbilical cord MSCs (HUC-MSCs) attenuated hepatic fibrosis by regulating miR-455-3p and its target gene. Significantly upregulated miRNA (miR-455-3p) was screened out by GEO datasets analysis and coculture HUC-MSCs with hepatic stellate cell (HSC) LX-2 cells. p21-activated kinase-2 (PAK2) was forecasted to be the target gene of miR-455-3p by bioinformatics analyses and confirmed by luciferase reporter assay. HUC-MSCs were transplanted into mice with carbon tetrachloride- (CCl4-) induced liver fibrosis, the result showed that HUC-MSC transplantation significantly ameliorated the severity of CCl4-induced liver fibrosis, attenuated collagen deposition, improved liver function by reducing the expression of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum, upregulated miR-455-3p, and suppressed PAK2 expression of liver tissue in mice. Taken together, our study suggests that HUC-MSCs inhibit the activation of HSCs and mouse CCl4-induced liver fibrosis by upregulation of miR-455-3p through targeting PAK2.

Highlights

Liver fibrosis and cirrhosis are common pathological processes of many chronic liver diseases, including chronic hepatitis B and C, alcoholic steatohepatitis, nonalcoholic steatohepatitis, and autoimmune hepatitis, which can eventually lead to liver failure or liver cancer
To ascertain whether HUC-Mesenchymal stem cells (MSCs) transplantation affects the proliferation of hepatic stellate cell (HSC), human HSC cell line LX-2 cells were cocultured with HUC-MSCs using a coculture transwell chamber
To investigate whether HUC-MSCs could influence HSC activation, LX-2 cells were cultured in the absence of serum for starvation and activated with transforming growth factor β1 (TGFβ1)

Summary

Introduction

Liver fibrosis and cirrhosis are common pathological processes of many chronic liver diseases, including chronic hepatitis B and C, alcoholic steatohepatitis, nonalcoholic steatohepatitis, and autoimmune hepatitis, which can eventually lead to liver failure or liver cancer. Hepatic stellate cells (HSCs) are widely accepted to be the fibrogenic cell type in the liver [1]. The characteristic of fibrosis is accompanied by the activation and proliferation of HSCs and increased production of excessive extracellular matrix [2, 3]. There is an urgent need to find a new alternative treatment strategy. Mesenchymal stem cells (MSCs) are multipotent stem cells, which can be isolated from bone marrow, adipose tissue, umbilical cord, and other tissues [5, 6]. Accumulating evidences suggest that exogenous MSC treatment could ameliorate HSC activation and liver fibrosis, differentiate into hepatic cells, and promote the recovery of liver function [9, 10]

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