Successful transplantation of human hepatic stem cells with restricted localization to liver using hyaluronan grafts§

Authors

  • Rachael A. Turner,

    1. Departments of Cell Biology and PhysiologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
    2. Departments of Biomedical EngineeringUniversity of North Carolina School of Medicine, Chapel Hill, NC
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  • Eliane Wauthier,

    1. Departments of Cell Biology and PhysiologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
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  • Oswaldo Lozoya,

    1. Departments of Cell Biology and PhysiologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
    2. Departments of Biomedical EngineeringUniversity of North Carolina School of Medicine, Chapel Hill, NC
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  • Randall McClelland,

    1. Departments of Cell Biology and PhysiologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
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  • James E. Bowsher,

    1. Department of Biomedical Engineering, Duke University School of Medicine, Durham, NC
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  • Claire Barbier,

    1. Departments of Cell Biology and PhysiologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
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    • Deceased.

  • Glenn Prestwich,

    1. Department of Medicinal Chemistry and Center for Therapeutic Biomaterials, University of Utah, Salt Lake City, UT
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  • Edward Hsu,

    1. Department of Biomedical Engineering, Duke University School of Medicine, Durham, NC
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  • David A. Gerber,

    1. Departments of SurgeryUniversity of North Carolina School of Medicine, Chapel Hill, NC
    2. Departments of Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC
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  • Lola M. Reid

    Corresponding author
    1. Departments of Cell Biology and PhysiologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
    2. Departments of Biomedical EngineeringUniversity of North Carolina School of Medicine, Chapel Hill, NC
    3. Departments of Program in Molecular Biology and BiotechnologyUniversity of North Carolina School of Medicine, Chapel Hill, NC
    4. Departments of Lineberger Cancer Center, University of North Carolina School of Medicine, Chapel Hill, NC
    • University of North Carolina School of Medicine, Campus Box 7038, Glaxo Building Rms 32-35, Chapel Hill, NC 27599
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    • fax: 919-966-6112


  • Potential conflict of interest: A patent on the grafting strategies has been filed, is owned by the University of North Carolina, and has been licensed to Vesta Therapeutics for eventual use in clinical programs. None of the authors have equity or a position in Vesta, and none are paid consulting fees by the company. Dr. Reid owns stock in, is a co-founder of, and holds intellectual property rights with Phoenix Sonap Biologicals. Dr. Prestwich is consultant for, received grants from, and holds intellectual property rights with Echelon Biosciences. He owns stock in, consults for, and holds intellectual property rights with BioTime. He owns stock in and holds intellectual property rights with Carbylan and SentrX Animal Care. He owns stock in, is an employee of, received grants from, and holds intellectual property rights with Glycominds.

  • This work was supported by grants from Vesta Therapeutics, the North Carolina Translational and Clinical Sciences Institute (Grant 2KR50905), the North Carolina Biotechnology Center, the National Institutes of Health (Grant CA016086), and the Department of Energy (Grant 03-SC-DOE-1017). Positron emission tomography studies were performed at the Duke Center for In Vivo Microscopy, a National Center for Research Resources Biomedical Technology Resource Center (P41 RR005959) and Small Animal Imaging Resource Program (U24 CA092656).

  • §

    Randall McClelland is currently affiliated with SciKon Innovation, Inc., Research Triangle Park, NC.

  • Edward Hsu is currently affiliated with the Department of Bioengineering, University of Utah, Salt Lake City, UT.

Abstract

Cell therapies are potential alternatives to organ transplantation for liver failure or dysfunction but are compromised by inefficient engraftment, cell dispersal to ectopic sites, and emboli formation. Grafting strategies have been devised for transplantation of human hepatic stem cells (hHpSCs) embedded into a mix of soluble signals and extracellular matrix biomaterials (hyaluronans, type III collagen, laminin) found in stem cell niches. The hHpSCs maintain a stable stem cell phenotype under the graft conditions. The grafts were transplanted into the livers of immunocompromised murine hosts with and without carbon tetrachloride treatment to assess the effects of quiescent versus injured liver conditions. Grafted cells remained localized to the livers, resulting in a larger bolus of engrafted cells in the host livers under quiescent conditions and with potential for more rapid expansion under injured liver conditions. By contrast, transplantation by direct injection or via a vascular route resulted in inefficient engraftment and cell dispersal to ectopic sites. Transplantation by grafting is proposed as a preferred strategy for cell therapies for solid organs such as the liver. (HEPATOLOGY 2013)

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