Abstract
Bone marrow-derived mesenchymal stem cells (BMSCs) can differentiate into hepatocyte-like cells (HLCs) to attenuate cirrhosis. Long noncoding RNA (lncRNA) SNHG1 has been demonstrated to orchestrate BMSC differentiation, whereas its role in cirrhosis remains elusive. Therefore, this study was performed to figure out whether lncRNA SNHG1 was involved in cirrhosis by affecting HLC differentiation of BMSCs. Mouse BMSCs were isolated, and the BMSC differentiation into HLCs was induced by hepatocyte growth factor (HGF). A cirrhotic mouse model was established using carbon tetrachloride and phenobarbital, followed by intravenous injection of BMSCs with manipulated expression of lncRNA SNHG1, microRNA (miR)-15a, and SMURF1. Subsequent to HGF induction, expression of hepatocyte-related genes, albumin secretion, and glycogen accumulation was increased in BMSCs, suggesting the differentiation of BMSCs into HLCs. Mechanistically, lncRNA SNHG1 bound to miR-15a that targeted SMURF1, and SMURF1 diminished ATG5 and Wnt5a expression by enhancing the ubiquitination of UVRAG. LncRNA SNHG1 or SMURF1 silencing or miR-15a overexpression promoted differentiation of BMSCs into HLCs and repressed cirrhosis of mice by upregulating ATG5 and Wnt5a via UVRAG. Conclusively, lncRNA SNHG1 silencing might facilitate HLC differentiation from mouse BMSCs and alleviate cirrhosis via the miR-15a/SMURF1/UVRAG/ATG5/Wnt5a axis.
Highlights
Cirrhosis is the ultimate pathological outcome of numerous chronic liver diseases, of which fibrosis is the precursor [1]
We found that Bone marrow-derived mesenchymal stem cells (BMSCs) without hepatocyte growth factor (HGF) induction barely expressed ALB, CK18, TTR, and AFP, whereas these genes were expressed in both NCTC 1469 hepatocytes and HGF-challenged BMSCs (Fig. 1C–F)
As reflected by enzymelinked immunosorbent assay (ELISA), BMSCs supplemented with HGF had enhanced ALB secretion, whereas BMSCs without HGF barely secreted ALB, suggesting that they did not differentiate toward hepatocytes (Fig. 1G)
Summary
Cirrhosis is the ultimate pathological outcome of numerous chronic liver diseases, of which fibrosis is the precursor [1]. Cirrhosis is attributed to alcoholism, nonalcoholic steatohepatitis, chronic hepatitis B virus, and hepatitis C virus infection [3]. Bone marrow-derived mesenchymal stem cell (BMSC)-based therapy has emerged as an attractive treatment regimen for cirrhosis [5, 6]. It has been widely documented that hepatocyte-like cells can be directly differentiated from BMSCs in vitro [7]. Hepatocyte-like cell (HLC) transplantation can be utilized as an effective therapy for cirrhosis [8]. It is imperative to figure out the mechanism underlying the alleviating effects of differentiation of BMSCs into HLCs on cirrhosis
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