Basic Study
Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jan 14, 2018; 24(2): 237-247
Published online Jan 14, 2018. doi: 10.3748/wjg.v24.i2.237
Transplantation of bone marrow-derived endothelial progenitor cells and hepatocyte stem cells from liver fibrosis rats ameliorates liver fibrosis
Ling Lan, Ran Liu, Ling-Yun Qin, Peng Cheng, Bo-Wei Liu, Bing-Yong Zhang, Song-Ze Ding, Xiu-Ling Li
Ling Lan, Bo-Wei Liu, Bing-Yong Zhang, Song-Ze Ding, Xiu-Ling Li, Department of Gastroenterology and Hepatology, the People’s Hospital of Zhengzhou University (the Henan Provincial People’s Hospital), Zhengzhou 450003, Henan Province, China
Ran Liu, Department of Oncology, Henan Provincial Rongjun Hospital, Xinxiang 453000, Henan Province, China
Ling-Yun Qin, Department of Gastroenterology and Hepatology, the Children’s Hospital of Zhengzhou, Zhengzhou 450003, Henan Province, China
Peng Cheng, Intensive Care Unit, the Second Affiliated Hospital of Luohe Medical College, Luohe 462000, Henan Province, China
Author contributions: Lan L and Liu R contributed equally to this study and are the co-first authors; Lan L and Liu R designed the study; Lan L, Liu R, Qin LY, Cheng P and Zhang BY performed the study; Lan L, Liu R and Qin LY wrote the paper; Liu BW and Zhang BY established the rat models; Ding SZ and Li XL collected and analyzed the data.
Supported by the National Natural Science Foundation of China, No. 30900598; the Basic and Advanced Technology Research Program of Henan Province, No. 142300410380; and the Medical Science and Technology Project of Henan Province, No. 201303211.
Institutional review board statement: The study was reviewed and approved by the Institutional Review Board of Henan Provincial People’s Hospital, China.
Institutional animal care and use committee statement: All procedures involving animals were reviewed and approved by the Institutional Animal Care and Use committee of the Animal Experiment Center of Henan Province, China [SCXK(Yu)2005-0001].
Conflict-of-interest statement: Potential conflicts of interest do not exist.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Ling Lan, PhD, MD, Associate Professor, Department of Gastroenterology and Hepatology, the People’s Hospital of Zhengzhou University (the Henan Provincial People’s Hospital), 7 Weiwu Road, Zhengzhou 450003, Henan Province, China. lanling95@163.com
Telephone: +86-371-65580603 Fax: +86-371-6596 4376
Received: September 30, 2017
Peer-review started: October 1, 2017
First decision: October 25, 2017
Revised: November 6, 2017
Accepted: November 22, 2017
Article in press: November 22, 2017
Published online: January 14, 2018
Processing time: 105 Days and 21.8 Hours
Abstract
AIM

To explore the effectiveness for treating liver fibrosis by combined transplantation of bone marrow-derived endothelial progenitor cells (BM-EPCs) and bone marrow-derived hepatocyte stem cells (BDHSCs) from the liver fibrosis environment.

METHODS

The liver fibrosis rat models were induced with carbon tetrachloride injections for 6 wk. BM-EPCs from rats with liver fibrosis were obtained by different rates of adherence and culture induction. BDHSCs from rats with liver fibrosis were isolated by magnetic bead cell sorting. Tracing analysis was conducted by labeling EPCs with PKH26 in vitro to show EPC location in the liver. Finally, BM-EPCs and/or BDHSCs transplantation into rats with liver fibrosis were performed to evaluate the effectiveness of BM-EPCs and/or BDHSCs on liver fibrosis.

RESULTS

Normal functional BM-EPCs from liver fibrosis rats were successfully obtained. The co-expression level of CD133 and VEGFR2 was 63.9% ± 2.15%. Transplanted BM-EPCs were located primarily in/near hepatic sinusoids. The combined transplantation of BM-EPCs and BDHSCs promoted hepatic neovascularization, liver regeneration and liver function, and decreased collagen formation and liver fibrosis degree. The VEGF levels were increased in the BM-EPCs (707.10 ± 54.32) and BM-EPCs/BDHSCs group (615.42 ± 42.96), compared with those in the model group and BDHSCs group (P < 0.05). Combination of BM-EPCs/BDHSCs transplantation induced maximal up-regulation of PCNA protein and HGF mRNA levels. The levels of alanine aminotransferase (AST), aspartate aminotransferase, total bilirubin (TBIL), prothrombin time (PT) and activated partial thromboplastin time in the BM-EPCs/BDHSCs group were significantly improved, to be equivalent to normal levels (P > 0.05) compared with those in the BDHSC (AST, TBIL and PT, P < 0.05) and BM-EPCs (TBIL and PT, P < 0.05) groups. Transplantation of BM-EPCs/BDHSCs combination significantly reduced the degree of liver fibrosis (staging score of 1.75 ± 0.25 vs BDHSCs 2.88 ± 0.23 or BM-EPCs 2.75 ± 0.16, P < 0.05).

CONCLUSION

The combined transplantation exhibited maximal therapeutic effect compared to that of transplantation of BM-EPCs or BDHSCs alone. Combined transplantation of autogenous BM-EPCs and BDHSCs may represent a promising strategy for the treatment of liver fibrosis, which would eventually prevent cirrhosis and liver cancer.

Keywords: Bone marrow; Endothelial progenitor cells; Liver stem cell; Cell transplantation; Liver fibrosis

Core tip: In addition to liver regeneration, hepatic neovascularization and endothelial/sinusoidal remodeling are critical factors for the treatment of liver fibrosis. Bone marrow-derived endothelial progenitor cells (BM-EPCs) have been shown to play a role in hepatic angiogenesis and to be beneficial in liver fibrosis. However, BM-EPCs are all derived from healthy individuals in recent studies. Here, we evaluated the feasibility of obtaining normal BM-EPCs from rats with liver fibrosis, and the effectiveness of combined transplantation of BM-EPCs and bone marrow-derived hepatocyte stem cells for treating liver fibrosis in order to achieve the dual effects of hepatic neovascularization and liver regeneration.