Date

8-2014

Document Type

Dissertation

Degree Name

Ph.D.

Department

Department of Cell, Developmental & Cancer Biology

Institution

Oregon Health & Science University

Abstract

Adult liver progenitor cells are biliary like epithelial cells that emerge only under injury conditions in the periportal region of the liver. They exhibit phenotypes of both hepatocytes and cholangiocytes. Experimental injury models in rodents designed to model this biliary progenitor proliferation have demonstrated that duct like “oval cells” act as progenitor cells and can differentiate into both hepatocytes and cholangiocytes. This finding suggested that the progenitor compartment represents a clinically important cell population that could be pharmacologically manipulated to improve liver function in advanced liver disease where mortality is high and few treatment options currently exist. Historically, bipotential oval cells were proposed to originate from a quiescent, reserve stem cell located at the interface between the bile ducts and hepatocytes in “the canal of Hering”. Nevertheless, the precise origin of liver progenitors has continued to be a matter of controversy and debate in the field for over 50 years.

The goal of this thesis is to understand the cellular mechanisms of liver regeneration in models of chronic liver injury. Specifically, I focus on the origin and function of putative liver stem/progenitor, a cell type whose function is disputed but tightly associated with chronic liver disease. I begin by reviewing the liver architecture, embryology of the liver, and histologic observations in human liver injury that have guided experimental efforts. Next, I explore the experimental systems used to look for the presence of liver stem/progenitors cells and the conclusions drawn from chronic injury models in rodents. I focus on the experimental evidence used to justify the liver stem cell hypothesis, a controversial but predominant theory in the field. The next three chapters focus on independent research I performed under the supervision of Dr. Markus Grompe. The first chapter of original research encompasses over 2 years of unpublished work developing in vitro systems to identify liver progenitor cells in mice and humans. The next chapter is adapted from an article published in the journal Hepatology. We utilize clonal lineage tracing to test the hypothesis that biliary duct derived liver progenitor cells are an important source of new hepatocytes in the injured mouse liver. The final research chapter (manuscript in peer review/revision at the time of this writing) explores the opposite hypothesis through lineage tracing techniques—namely, that hepatocytes themselves are the source of progenitor]like ductal cells. The chapter leads to a unifying hypothesis for the thesis as a whole—that hepatocyte metaplasia mimics liver stem cell activation. We also propose a new hypothesis to explain observations of cellular plasticity in experimental rodent injury models and human disease called the decoy metaplasia hypothesis. With the decoy metaplasia hypothesis in mind, I use the final chapter to discuss how several fast moving areas of liver biology may provide new therapeutic strategies for improving liver regeneration and liver function in patients with liver disease.

Identifier

doi:10.6083/M4TB15NP

School

School of Medicine

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