Mesenchymal Stem Cells Overexpressing C-X-C Chemokine Receptor Type 4 Improve Early Liver Regeneration of Small-for-Size Liver Grafts

Authors

  • Zhiyong Du,

    Corresponding author
    1. Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, People's Republic of China
    • Department of General Surgery, Xinhua Hospital, Shanghai, People's Republic of China
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    • These authors contributed equally to this work.

  • Cuifeng Wei,

    Corresponding author
    1. Department of Endocrinology, Jingmen First Hospital, Jingmen, People's Republic of China
    • Department of General Surgery, Xinhua Hospital, Shanghai, People's Republic of China
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    • These authors contributed equally to this work.

  • Jiqi Yan,

    Corresponding author
    1. Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, People's Republic of China
    • Department of General Surgery, Xinhua Hospital, Shanghai, People's Republic of China
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    • These authors contributed equally to this work.

  • Baosan Han,

    1. Department of General Surgery, Xinhua Hospital, Shanghai, People's Republic of China
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  • Mingjun Zhang,

    1. Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, People's Republic of China
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  • Chenghong Peng,

    1. Department of General Surgery, Ruijin Hospital, Shanghai Jiaotong University Medical School, Shanghai, People's Republic of China
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  • Yingbin Liu

    1. Department of General Surgery, Xinhua Hospital, Shanghai, People's Republic of China
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  • This work was supported by grants from the Science and Technology Commission of Shanghai Municipality (Key Basic Research Project 07JC14040 and Project 09ZR1418600) and the National Natural Science Foundation of China (81070358).

Address reprint requests to Chenghong Peng, M.D., F.A.C.S., Department of General Surgery, Ruijin Hospital Shanghai Jiaotong University Medical School, Shanghai 200025, People's Republic of China. E-mail: chhpeng@188.com or Yingbin Liu, M.D., Department of General Surgery, Xinhua Hospital, Shanghai Jiaotong University Medical School, Shanghai 200092, People's Republic of China. E-mail: laoniulyb@163.com

Abstract

Mesenchymal stem cell (MSC) therapy can prevent hepatic parenchymal cell loss and promote tissue repair. However, poor MSC engraftment is one of the primary barriers to the effectiveness of cell therapy because culture-expanded MSCs progressively down-regulate C-X-C chemokine receptor type 4 (CXCR4) expression and lose their ability to migrate toward a concentration gradient of stromal cell–derived factor 1a (SDF1a). In this study, we investigated whether a CXCR4-MSC infusion could protect hepatocytes and stimulate regeneration in 50% reduced size liver transplantation (RSLT). Rats that underwent 50% RSLT were randomly divided into 3 groups: a phosphate-buffered solution group (PBS), a green fluorescent protein (GFP)–MSC group, and a CXCR4-MSC group. Rats received 1 mL of PBS with or without a resuspension of GFP-MSCs or CXCR4-MSCs. The factors secreted by MSCs, the graft function, the apoptosis and proliferation of hepatocytes, the efficacy of MSC engraftment, and the expression of SDF1α, albumin (Alb), and cytokeratin 18 (CK18) in engrafted GFP-positive MSCs were assessed. A systemic infusion of GFP-MSCs led to a reduction of the release of liver injury biomarkers and apoptosis of hepatocytes; CXCR4 overexpression did not further reduce the liver injury. However, CXCR4 overexpression enhanced MSC engraftment in liver grafts, improved the effect on the proliferation of hepatocytes, and thus provided a significant 1-week survival benefit. SDF1α expression in grafts was elevated after transplanted CXCR4-MSCs were recruited to the remnant liver. However, engrafted MSCs did not express the markers of hepatocytes, including Alb and CK18, in vivo 168 hours after transplantation. CXCR4 overexpression enhanced the mobilization and engraftment of MSCs into small-for-size liver grafts, in which these cells promoted the early regeneration of the remnant liver not by direct differentiation but perhaps by a paracrine mechanism. Liver Transpl 19:215-225, 2013. © 2012 AASLD.

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