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In vitro modeling of congenital and acquired liver diseases

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title
In vitro modeling of congenital and acquired liver diseases
author
Brovold, Matthew Dean
abstract
One of the goals of liver bioengineering is to develop in vitro platforms in order to study the complexities of development, disease, and drug metabolism in a fashion that is highly replicative of in vivo processes, but superior in terms of speed, cost, and reproducibility. One such approach is through bioengineered 3D organoids. Though the use of a variety of substrates such as acellular tissue scaffolds or hydrogels of various compositions, cells are cultured and allowed to interact with the substrate and with other cells. Importantly, stromal cells of the liver constitute only a small percentage of the liver itself but exert the most profound influence on both liver organogenesis and pathology. Approaches using organoids to study liver disease often fail to consider the influence of stromal cells. This thesis aims to explore the role of stromal cells, specifically the hepatic stellate cell, in the study of congenital and acquired liver diseases associated with fibrosis to better understand the causes and the treatments of such disorders. To this end, we investigated the effect of inhibition of normal stromal cell signaling on development, which clinically generates fibrosis. Next, we studied the influence of a fibrotic environment induced by resident stromal cells on the developing liver. Finally, we determined the range of fibrotic phenotypes stromal cells are able create within an organoid. Collectively, the findings in this thesis exemplify the importance of stromal cell inclusion within bioengineered 3D organoids to effectively study liver disease in vitro.
subject
Biliary development
fibrotic organoid
Hepatic stellate cell
liver fibrosis
organoid
contributor
Soker, Shay (committee chair)
Alameida-Porada, Graca (committee member)
Friedman, Scott (committee member)
Marini, Frank (committee member)
Skardal, Aleksander (committee member)
date
2020-05-29T08:35:53Z (accessioned)
2020-11-28T09:30:11Z (available)
2020 (issued)
degree
Molecular Medicine and Translational Science (discipline)
embargo
2020-11-28 (terms)
identifier
http://hdl.handle.net/10339/96811 (uri)
language
en (iso)
publisher
Wake Forest University
type
Dissertation

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