Role of stem cell factor and granulocyte colony-stimulating factor in remodeling during liver regeneration

Authors

  • Fanyin Meng,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
    2. Division of Research and Education, Scott & White Hospital, Temple, TX
    3. Research Service, Central Texas Veterans Health Care System, Temple, TX
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    • *

      These authors contributed equally to the manuscript for this article.

  • Heather Francis,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
    2. Division of Research and Education, Scott & White Hospital, Temple, TX
    3. Research Service, Central Texas Veterans Health Care System, Temple, TX
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    • *

      These authors contributed equally to the manuscript for this article.

  • Shannon Glaser,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
    2. Research Service, Central Texas Veterans Health Care System, Temple, TX
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  • Yuyan Han,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
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  • Sharon DeMorrow,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
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  • Allison Stokes,

    1. Division of Research and Education, Scott & White Hospital, Temple, TX
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  • Dustin Staloch,

    1. Division of Research and Education, Scott & White Hospital, Temple, TX
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  • Julie Venter,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
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  • Melanie White,

    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
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  • Yoshiyuki Ueno,

    1. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan
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  • Lola M. Reid,

    1. Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, NC
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  • Gianfranco Alpini

    Corresponding author
    1. Department of Medicine and Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, and Scott & White Hospital, Temple, TX
    2. Research Service, Central Texas Veterans Health Care System, Temple, TX
    • Department of Medicine, Scott & White Digestive Disease Research Center, Texas A&M Health Science Center, College of Medicine, Olin E. Teague Medical Center, 1901 South 1st Street, Building 205, 1R60, Temple, TX 76504
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    • fax: 254-743-0378


  • Potential conflict of interest: Nothing to report.

  • This study was supported by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White, a Veterans Affairs Research Career Scientist Award, a Veterans Award Merit Award, and National Institutes of Health grants DK58411 and DK76898 (to G.A.).

Abstract

Functional pluripotent characteristics have been observed in specific subpopulations of hepatic cells that express some of the known cholangiocyte markers. Although evidence indicates that specific cytokines, granulocyte macrophage colony-stimulating factors (GM-CSFs), and stem cell factors (SCFs) may be candidate treatments for liver injury, the role of these cytokines in intrahepatic biliary epithelium remodeling is unknown. Thus, our aim was to characterize the specific cytokines that regulate the remodeling potentials of cholangiocytes after 70% partial hepatectomy (PH). The expression of the cytokines and their downstream signaling molecules was studied in rats after 70% PH by immunoblotting and in small and large murine cholangiocyte cultures (SMCCs and LMCCs) by immunocytochemistry and real-time polymerase chain reaction (PCR). There was a significant, stable increase in SCF and GM-CSF levels until 7 days after PH. Real-time PCR analysis revealed significant increases of key remodeling molecules, such as S100 calcium-binding protein A4 (S100A4) and miR-181b, after SCF plus GM-CSF administration in SMCCs. SMCCs produced significant amounts of soluble and bound SCFs and GM-CSFs in response to transforming growth factor-beta (TGF-β). When SMCCs were incubated with TGF-β plus anti-SCF+GM-CSF antibodies, there was a significant decrease in S100A4 expression. Furthermore, treatment of SMCCs with SCF+GM-CSF significantly increased matrix metalloproteinases (MMP-2 and MMP-9) messenger RNA as well as miR-181b expression, along with a reduction of metalloproteinase inhibitor 3. Levels of MMP-2, MMP-9, and miR-181b were also up-regulated in rat liver and isolated cholangiocytes after PH. Conclusion: Our data suggest that altered expression of SCF+GM-CSF after PH can contribute to biliary remodeling (e.g., post-transplantation) by functional deregulation of the activity of key signaling intermediates involved in cell expansion and multipotent differentiation. (HEPATOLOGY 2012;;55:209–221)

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