STRATEGIES FOR EX VIVO MODELS OF HUMAN HEPATOPOIESIS DEMONSTRATING ZONATION OF PHENOTYPIC TRAITS Public Deposited

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  • March 19, 2019
Creator
  • Hanson, Ariel
    • Affiliation: School of Medicine, UNC/NCSU Joint Department of Biomedical Engineering
Abstract
  • Constructing a precise in vitro or ex vivo model of liver has been a goal in academia and industry research for decades. Although most current liver models have made use of murine or rodent liver cells, these have been shown to be inadequate to predict human liver toxicology or pathophysiology, resulting in a need for more superior human models. This body of work details the development of stable and functional human liver tissue established ex vivo by seeding human fetal liver cells into three-dimensional liver biomatrix scaffolds. One of the difficulties of developing a tissue-engineered liver using organ decellularization strategies is retaining patent microvascular structures crucial for nutrient access and functionality of the tissue. A novel form of 3-D functional ultrasound imaging has been developed enabling non-destructive assessment of extracellular matrix scaffolds, ones prepared by decellularization protocols and intended for recellularization to yield tissue- engineered livers. Once the matrix remnants of the liver vasculature were confirmed to be patent, human fetal liver stem/progenitor cells could be seeded into the biomatrix. Human fetal liver cells seeded into the scaffolds attached within hours and demonstrated differentiated functions and liver histology and ultrastructure within less than a week. The tissue that formed remained functional for weeks thereafter by perfusion with a serum free, hormonally defined medium optimized for maintenance of mature liver traits. The strategies utilized in this body of work resulted in rapid establishment of functional human liver tissue with results not observed by any monolayer or organoid culture system or by any other recellularized scaffold preparations. Other fetal or adult liver cells have required transplantation in vivo to enable achievement of significant levels of adult liver functions. By contrast, the liver biomatrix scaffolds reseeded with the stem/progenitors from human fetal livers yielded highly functional liver tissue entirely ex vivo and in less than a week.
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  • In Copyright
Advisor
  • Macdonald, Jeffrey
  • Loboa, Elizabeth
  • Dayton, Paul
  • Reid, Lola
  • Gerber, David
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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