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Determining the Effects of Wnt Signaling in the Alleviation of Cholestasis Via the Promotion of Hepatocyte Transdifferentiation and Cholangiocyte Proliferation

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Kosar, Karis Pearlkpk21@pitt.edukpk210000-0002-8799-1964
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorNejak-Bowen, Kariknnst5@pitt.eduknnst50000-0001-6051-5338
Committee CoChairSoto-Gutiérrez, Alejandroals208@pitt.eduals2080000-0002-9838-1862
Committee MemberDavidson, Lancelad43@pitt.edulad430000-0002-2956-0437
Committee MemberMonga, Satdarshan P. S.smonga@pitt.edusmonga0000-0002-8437-3378
Committee MemberOertel, Michaelmio19@pitt.edumio19
Committee MemberShin, Donghundonghuns@pitt.edudonghuns0000-0002-7975-9014
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


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