Kosar, Karis Pearl
(2021)
Determining the Effects of Wnt Signaling in the Alleviation of Cholestasis Via the Promotion of Hepatocyte Transdifferentiation and Cholangiocyte Proliferation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Primary sclerosing cholangitis (PSC), is a chronic cholestatic disease that causes bile duct inflammation and fibrosis, and results in end-stage liver disease and reduced life expectancy. Therefore, an effective treatment for PSC is needed. Previously we identified specific Wnt proteins (Wnt7a, a canonical signaling ligand, and Wnt7b, a noncanonical signaling ligands) upregulated in the cholangiocytes during cholestatic liver injury and found mice lacking Wnt secretion from hepatocytes and cholangiocytes showed fewer hepatocytes expressing cholangiocyte markers, proliferating cholangiocytes, and high mortality in response to DDC diet. These findings led us to two hypotheses: 1) Canonical Wnt/β-catenin signaling induces hepatocyte-to-cholangiocyte transdifferentiation, which could alleviate cholestatic injury caused by PSC, and 2) Wnt7b induces cholangiocyte proliferation, which if knocked out would induce more severe cholestatic injury caused by PSC. After testing these hypotheses, we found that β-catenin signaling does induce hepatocyte-to-cholangiocyte reprogramming, thereby alleviating biliary injury. We also found that mice lacking Wnt7b in only the cholangiocytes, and mice lacking Wnt7b in both hepatocyte and cholangiocyte compartments did in fact have decreased cholangiocyte proliferation, but this did not result in increased biliary injury. Instead, this inability of the cholangiocytes to proliferate promoted hepatocytes to adopt a cholangiocyte-like phenotype, which resulted in the alleviation of cholestatic injury. Overall, our work has elucidated two methods to induce hepatocyte-to-cholangiocyte transdifferentiation which could be used to establish a groundwork for potential PSC treatments.
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Details
| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
21 August 2021 |
| Date Type: |
Publication |
| Defense Date: |
5 May 2021 |
| Approval Date: |
21 August 2021 |
| Submission Date: |
3 August 2021 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
154 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Cellular and Molecular Pathology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
bile ducts, primary sclerosing cholangitis, liver, wnt, beta catenin |
| Date Deposited: |
22 Aug 2021 01:46 |
| Last Modified: |
22 Aug 2021 01:46 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/41566 |
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