Original Article
Copyright ©2014 Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2014; 20(40): 14884-14894
Published online Oct 28, 2014. doi: 10.3748/wjg.v20.i40.14884
Targeted migration of mesenchymal stem cells modified with CXCR4 to acute failing liver improves liver regeneration
Hu-Cheng Ma, Xiao-Lei Shi, Hao-Zhen Ren, Xian-Wen Yuan, Yi-Tao Ding
Hu-Cheng Ma, Xiao-Lei Shi, Hao-Zhen Ren, Xian-Wen Yuan, Yi-Tao Ding, Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, Nanjing 210008, Jiangsu Province, China
Xiao-Lei Shi, Hao-Zhen Ren, Xian-Wen Yuan, Yi-Tao Ding, Key Medical Center for Hepatobiliary Diseases of Jiangsu Province, Nanjing 210008, Jiangsu Province, China
Author contributions: Ma HC and Shi XL contributed equally to this work and designed the study; Ma HC and Yuan XW performed the majority of experiments; Shi XL and Ding YT provided vital reagents and financial support for this work; Yuan XW and Ren HZ analyzed data; Ma HC wrote the manuscript; Shi XL and Ding YT reviewed the manuscript.
Supported by National Natural Science Foundation of China, 81170418; Natural Science Foundation of Jiangsu Province, BK20131084; and University Graduate Innovation Program of Jiangsu Province, CXZZ13_0062
Correspondence to: Yi-Tao Ding, MD, Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital of Nanjing University Medical School, No. 321 Zhongshan Road, Nanjing 210008, Jiangsu Province, China. yitaoding@hotmail.com
Telephone: +86-25-83107080 Fax: +86-25-83105987
Received: January 9, 2014
Revised: March 31, 2014
Accepted: May 12, 2014
Published online: October 28, 2014
Processing time: 293 Days and 9.3 Hours
Abstract

AIM: To improve the colonization rate of transplanted mesenchymal stem cells (MSCs) in the liver and effect of MSC transplantation for acute liver failure (ALF).

METHODS: MSC was modified with the chemokine CXC receptor 4 (CXCR4) gene (CXCR4-MSC) or not (Null-MSC) through lentiviral transduction. The characteristics of CXCR4-MSCs and Null-MSCs were determined by real-time quantitative polymerase chain reaction, Western blotting and flow cytometry. CXCR4-MSCs and Null-MSCs were infused intravenously 24 h after administration of CCl4 in nude mice. The distribution of the MSCs, survival rates, liver function, hepatocyte regeneration and growth factors of the recipient mice were analyzed.

RESULTS: In vitro, CXCR4-MSCs showed better migration capability toward stromal cell-derived factor-1α and a protective effect against thioacetamide in hepatocytes. In vivo imaging showed that CXCR4-MSCs migrated to the liver in larger numbers than Null-MSCs 1 and 5 d after ALF. Higher colonization led to a longer lifetime and better liver function. Either CXCR4-MSCs or Null-MSCs exhibited a paracrine effect through secreting hepatocyte growth factor and vascular endothelial growth factor. Immunohistochemical analysis of Ki-67 showed increased cell proliferation in the damaged liver of CXCR4-MSC-treated animals.

CONCLUSION: Genetically modified MSCs expressing CXCR4 showed greater colonization and conferred better functional recovery in damaged liver.

Keywords: Acute liver failure; Cell transplantation; Chemokine CXC receptor 4; Mesenchymal stem cells; Cell mobilization

Core tip: Mesenchymal stem cell (MSC) transplantation is an effective therapy for acute liver failure (ALF), and is expected to be an alternative to liver transplantation. Many current studies have exhibited poor efficiency of MSC transplantation due to low colonization in the failing liver. We modified MSCs with the chemokine CXC receptor 4 (CXCR4) gene to promote the colonization of MSCs in failing liver depending on the stromal cell-derived factor-1α/CXCR4 axis. In vivo imaging showed that CXCR4-MSCs migrated to the liver in higher numbers than Null-MSCs 1 and 5 d after ALF. Greater colonization led to a longer lifetime and better liver function.