Repopulation of the fibrotic/cirrhotic rat liver by transplanted hepatic stem/progenitor cells and mature hepatocytes

Authors

  • Mladen I. Yovchev,

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, New York, NY
    2. Department of Medicine (Division of Gastroenterology and Liver Diseases), Albert Einstein College of Medicine of Yeshiva University, New York, NY
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  • Yuhua Xue,

    1. Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pittsburgh, PA
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  • David A. Shafritz,

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, New York, NY
    2. Department of Medicine (Division of Gastroenterology and Liver Diseases), Albert Einstein College of Medicine of Yeshiva University, New York, NY
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  • Joseph Locker,

    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, New York, NY
    2. Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pittsburgh, PA
    3. Department of Pathology, Albert Einstein College of Medicine of Yeshiva University, New York, NY
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  • Michael Oertel

    Corresponding author
    1. Marion Bessin Liver Research Center, Albert Einstein College of Medicine of Yeshiva University, New York, NY
    2. Department of Medicine (Division of Gastroenterology and Liver Diseases), Albert Einstein College of Medicine of Yeshiva University, New York, NY
    3. Department of Pathology (Division of Experimental Pathology), University of Pittsburgh, Pittsburgh, PA
    4. McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA
    • Address reprint requests to: Michael Oertel, Ph.D., University of Pittsburgh, School of Medicine, Dept. of Pathology, 200 Lothrop St., BST S-404, Pittsburgh, PA 15261. E-mail: mio19@pitt.edu; fax: 412-648-1916.

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  • Potential conflict of interest: Nothing to report.

  • Supported by NIH grant R01 DK090325 (to M.O.) and a Pilot and Feasibility Study (to M.O.) from P30 DK041296 (to D.A.S.), and R01 DK017609 (to D.A.S.).

Abstract

Considerable progress has been made in developing antifibrotic agents and other strategies to treat liver fibrosis; however, significant long-term restoration of functional liver mass has not yet been achieved. Therefore, we investigated whether transplanted hepatic stem/progenitor cells can effectively repopulate the liver with advanced fibrosis/cirrhosis. Stem/progenitor cells derived from fetal livers or mature hepatocytes from DPPIV+ F344 rats were transplanted into DPPIV rats with thioacetamide (TAA)-induced fibrosis/cirrhosis; rats were sacrificed 1, 2, or 4 months later. Liver tissues were analyzed by histochemistry, hydroxyproline determination, reverse-transcription polymerase chain reaction (RT-PCR), and immunohistochemistry. After chronic TAA administration, DPPIV F344 rats exhibited progressive fibrosis, cirrhosis, and severe hepatocyte damage. Besides stellate cell activation, increased numbers of stem/progenitor cells (Dlk-1+, AFP+, CD133+, Sox-9+, FoxJ1+) were observed. In conjunction with partial hepatectomy (PH), transplanted stem/progenitor cells engrafted, proliferated competitively compared to host hepatocytes, differentiated into hepatocytic and biliary epithelial cells, and generated new liver mass with extensive long-term liver repopulation (40.8 ± 10.3%). Remarkably, more than 20% liver repopulation was achieved in the absence of PH, associated with reduced fibrogenic activity (e.g., expression of alpha smooth muscle actin, platelet-derived growth factor receptor β, desmin, vimentin, tissue inhibitor of metalloproteinase-1) and fibrosis (reduced collagen). Furthermore, hepatocytes can also replace liver mass with advanced fibrosis/cirrhosis, but to a lesser extent than fetal liver stem/progenitor cells. Conclusion: This study is a proof of principle demonstration that transplanted epithelial stem/progenitor cells can restore injured parenchyma in a liver environment with advanced fibrosis/cirrhosis and exhibit antifibrotic effects. (Hepatology 2014;58:284–295)

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