Long noncoding RNA SNHG1 silencing accelerates hepatocyte-like cell differentiation of bone marrow-derived mesenchymal stem cells to alleviate cirrhosis via the microRNA-15a/SMURF1/UVRAG axis

Jia Sun; Xuedong Sun; Sean Hu; Maoqiang Wang; Na Ma; Junhui Chen; Feng Duan

doi:10.1038/s41420-022-00850-8

Long noncoding RNA SNHG1 silencing accelerates hepatocyte-like cell differentiation of bone marrow-derived mesenchymal stem cells to alleviate cirrhosis via the microRNA-15a/SMURF1/UVRAG axis

Cell Death Discov. 2022 Feb 22;8(1):77. doi: 10.1038/s41420-022-00850-8.

Authors

Jia Sun^#^{1

2}, Xuedong Sun^#³, Sean Hu¹, Maoqiang Wang³, Na Ma⁴, Junhui Chen², Feng Duan⁵

Affiliations

¹ Shenzhen Beike Biotechnology Research Institute, Shenzhen, 518057, P.R. China.
² Intervention and Cell Therapy Center, Shenzhen Hospital of Peking University, Shenzhen, 518057, P. R. China.
³ Department of Interventional Radiology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, P.R. China.
⁴ Department of Radiotherapy, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, P.R. China.
⁵ Department of Interventional Radiology, the First Medical Center, Chinese PLA General Hospital, Beijing, 100853, P.R. China. duanfeng@vip.sina.com.

^# Contributed equally.

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.