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Investigating the Mechanisms of Hepatocyte or Biliary Epithelial Cell-Mediated Liver Regeneration

Russell, Jacquelyn (2019) Investigating the Mechanisms of Hepatocyte or Biliary Epithelial Cell-Mediated Liver Regeneration. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

The liver performs a wide array of functions such that it is indispensable for survival. Uniquely, the liver is the only human internal organ capable of regeneration. Failure of liver regeneration is thought to induce progression of chronic liver disease (CLD) to cirrhosis and end-stage liver disease, which is currently the 12th leading cause of death in the U.S. The only current treatment for end-stage liver disease is a liver transplant, for which there is a major dearth of donor organs. Therefore, understanding the molecular mechanisms underlying liver regeneration could lead to the development of desperately needed new therapies for liver disease. There are two main epithelial cell types in the liver: hepatocytes and biliary epithelial cells (BECs). Typically, liver regeneration after an acute injury is mediated by proliferation of hepatocytes. This is the case after partial hepatectomy (PHx), where 2/3 of the liver is surgically removed. We identified a role for bromodomain and extraterminal (BET) proteins in driving hepatocyte proliferation after PHx. BET proteins are a family of chromatin readers that interact with the basic transcriptional machinery to promote expression of virtually all genes. One pathway that we found to be especially sensitive to BET protein inhibition post-PHx was the Wnt/β-catenin signaling pathway, which is an important pathway in both liver development and multiple models of liver regeneration. One of these models involves liver regeneration when hepatocyte proliferation is impaired, a model in which BECs are theorized to differentiate into hepatocytes to mediate liver regeneration. We demonstrated that mice which lack liver-specific Wnt/β-catenin signaling (KO mice) exposed to choline-deficient, ethionine-supplemented (CDE) diet-induced liver injury have impaired hepatocyte proliferation. Furthermore, we utilized genetic lineage tracing of both hepatocytes and BECs to prove that BECs differentiate into hepatocytes in KO mice but not their wild-type counterparts following CDE diet-induced liver injury and recovery. Overall, our work has elucidated important signaling pathways driving liver regeneration in multiple models of liver injury and sets the stage for future work to identify clinically-relevant treatments which can enhance hepatic repair.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Russell, Jacquelynjor76@pitt.edujor760000-0001-9928-2869
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairNejak-Bowen, Kariknnst5@pitt.eduknnst5
Committee MemberMichalopoulos, Georgemichalopoulosgk@upmc.edumichalopoulosgk
Committee MemberDonghun, Shindonghuns@pitt.edudonghuns
Committee MemberSoto-Gutiérrez, Alejandroals208@pitt.eduals208
Committee MemberBrown, Bryanbrownb@upmc.edubrownb
Thesis AdvisorMonga, Satdarshansmonga@pitt.edusmonga
Date: 9 August 2019
Date Type: Publication
Defense Date: 3 May 2019
Approval Date: 9 August 2019
Submission Date: 18 June 2019
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 161
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Pathology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: Hepatocyte, Biliary Epithelial Cell, β-catenin
Date Deposited: 10 Aug 2019 03:29
Last Modified: 10 Aug 2019 03:29
URI: http://d-scholarship.pitt.edu/id/eprint/36956

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