Original Article
Copyright ©2010 Baishideng. All rights reserved.
World J Gastroenterol. Jul 14, 2010; 16(26): 3267-3278
Published online Jul 14, 2010. doi: 10.3748/wjg.v16.i26.3267
Identification of cytokines involved in hepatic differentiation of mBM-MSCs under liver-injury conditions
Xue-Jun Dong, Hui Zhang, Ruo-Lang Pan, Li-Xin Xiang, Jian-Zhong Shao
Xue-Jun Dong, Hui Zhang, Molecular Medicine Center of Shaoxing People’s Hospital, Shaoxing 312000, Zhejiang Province, China; School of Laboratory Medicine and Life Science, Wenzhou Medical College, Wenzhou 325035, Zhejiang Province, China
Ruo-Lang Pan, Li-Xin Xiang, Jian-Zhong Shao, College of Life Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China; Key Laboratory for Cell and Gene Engineering of Zhejiang Province, Hangzhou 310058, Zhejiang Province, China
Author contributions: Dong XJ, Xiang LX and Shao JZ designed the research, analyzed the data and edited the manuscript; Zhang H and Pan RL performed the research and edited the manuscript.
Supported by The Grant of Medicine and Health Key Projects of Zhejiang Province, Science and Technology Fund of Ministry of Health of the People’s Republic of China, No. WKJ2007-2-037; Shaoxing Key Project for Science and Technology, No. 2007A23008; the Natural Science Foundation of Zhejiang Province, China, No. Y2090337
Correspondence to: Jian-Zhong Shao, Professor, College of Life Sciences, Zhejiang University, Hangzhou 310058, Zhejiang Province, China. shaojz@zju.edu.cn
Telephone: +86-571-88206582 Fax: +86-571-88206582
Received: March 23, 2010
Revised: April 26, 2010
Accepted: May 3, 2010
Published online: July 14, 2010
Abstract

AIM: To identify the key cytokines involved in hepatic differentiation of mouse bone marrow mesenchymal stem cells (mBM-MSCs) under liver-injury conditions.

METHODS: Abdominal injection of CCl4 was adopted to duplicate a mouse acute liver injury model. Global gene expression analysis was performed to evaluate the potential genes involved in hepatic commitment under liver-injury conditions. The cytokines involved in hepatic differentiation of mBM-MSCs was functionally examined by depletion experiment using specific antibodies, followed by rescue experiment and direct inducing assay. The hepatic differentiation was characterized by the expression of hepatic lineage genes and proteins, as well as functional features.

RESULTS: Cytokines potentially participating in hepatic fate commitment under liver-injury conditions were initially measured by microarray. Among the up-regulated genes determined, 18 cytokines known to closely relate to liver growth, repair and development, were selected for further identification. The fibroblast growth factor-4 (FGF-4), hepatocyte growth factor (HGF) and oncostatin M (OSM) were finally found to be involved in hepatic differentiation of mBM-MSCs under liver-injury conditions. Hepatic differentiation could be dramatically decreased after removing FGF-4, HGF and OSM from the liver-injury conditioned medium, and could be rescued by supplementing these cytokines. The FGF-4, HGF and OSM play different roles in the hepatic differentiation of mBM-MSCs, in which FGF-4 and HGF are essential for the initiation of hepatic differentiation, while OSM is critical for the maturation of hepatocytes.

CONCLUSION: FGF-4, HGF and OSM are the key cytokines involved in the liver-injury conditioned medium for the hepatic differentiation of mBM-MSCs.

Keywords: Hepatic differentiation, Mouse bone marrow mesenchymal stem cells, Inducing cytokines, Fibroblast growth factor-4, Hepatocyte growth factor, Oncostatin M