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Human hepatic stem cell and maturational liver lineage biology

Authors

  • Rachael Turner,

    1. Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, NC
    2. Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, NC
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    • R. Turner & L.M. Reid did the majority of the writing & editing of the review. O. Lozoya prepared the sections on mechanical effects on cells, & Y. Wang contributed those on regulation by paracrine signaling. Comments on biliary tree biology & cholangiocytes were written & edited by D. Alvaro, E. Gaudio, V. Cardinale, & G. Alpini, & those on biliary tree stem cells were written by L.M. Reid, Y. Wang & V. Cardinale. Schematic figures were drawn by R. Turner & G. Mendel. C. Barbier & E. Wauthier helped edit the review.

    • Senior coauthors.

  • Oswaldo Lozoya,

    1. Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, NC
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  • Yunfang Wang,

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

    1. Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
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  • Eugenio Gaudio,

    1. Department of Human Anatomy, University of Rome, Rome, Italy
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  • Gianfranco Alpini,

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

    1. Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, NC
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  • Eliane Wauthier,

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

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

    1. Division of Gastroenterology, Department of Clinical Medicine, University of Rome, Rome, Italy
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    • Senior coauthors.

  • Lola M. Reid

    Corresponding author
    1. Department of Cell and Molecular Physiology, University of North Carolina School of Medicine, Chapel Hill, NC
    2. Department of Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, NC
    3. Program in Molecular Biology and Biotechnology, University of North Carolina School of Medicine, Chapel Hill, NC
    • UNC School of Medicine, Campus Box 7038, Glaxo Building Rms. 32-35, Chapel Hill, NC 27599
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    • Senior coauthors.


  • Funding for the investigators at UNC derived from NIH grants (DK52851, AA014243, IP30-DK065933), a DOE grant (DE-FG02-02ER-63477), & sponsored research grants from Vesta Therapeutics (Bethesda, MD), Vertex Pharmaceuticals (Cambridge, MA), & GigaCyte (Branford, CT). D. Alvaro is supported by MIUR (Italian Minister of University & Research) grants PRIN #2007, prot.2007HPT7BA-003 & by Federate Atheneaum funds from the University “Sapienza” of Rome. Dr. Gaudio was supported by MIUR grants PRIN#2007, prot. 2007HPT7BA_001 & Federate Atheneaum funds from the University “Sapienza” of Rome. Dr. Alpini is supported by the Dr. Nicholas C. Hightower Centennial Chair of Gastroenterology from Scott & White Hospital, a VA Research Scholar Award, a VA Merit Award, & NIH grants DK062975, K76898, & DK58411.

  • fax: (919) 966-6112

Abstract

Livers are comprised of maturational lineages of cells beginning extrahepatically in the hepato-pancreatic common duct near the duodenum and intrahepatically in zone 1 by the portal triads. The extrahepatic stem cell niches are the peribiliary glands deep within the walls of the bile ducts; those intrahepatically are the canals of Hering in postnatal livers and that derive from ductal plates in fetal livers. Intrahepatically, there are at least eight maturational lineage stages from the stem cells in zone 1 (periportal), through the midacinar region (zone 2), to the most mature cells and apoptotic cells found pericentrally in zone 3. Those found in the biliary tree are still being defined. Parenchymal cells are closely associated with lineages of mesenchymal cells, and their maturation is coordinated. Each lineage stage consists of parenchymal and mesenchymal cell partners distinguishable by their morphology, ploidy, antigens, biochemical traits, gene expression, and ability to divide. They are governed by changes in chromatin (e.g., methylation), gradients of paracrine signals (soluble factors and insoluble extracellular matrix components), mechanical forces, and feedback loop signals derived from late lineage cells. Feedback loop signals, secreted by late lineage stage cells into bile, flow back to the periportal area and regulate the stem cells and other early lineage stage cells in mechanisms dictating the size of the liver mass. Recognition of maturational lineage biology and its regulation by these multiple mechanisms offers new understandings of liver biology, pathologies, and strategies for regenerative medicine and treatment of liver cancers. (HEPATOLOGY 2011;)

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