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EMERGING ROLES OF PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA IN CHRONIC LIVER INJURY: POTENTIAL THERAPEUTIC TARGET IN HEPATIC FIBROSIS

Kikuchi, Alexander (2017) EMERGING ROLES OF PLATELET-DERIVED GROWTH FACTOR RECEPTOR ALPHA IN CHRONIC LIVER INJURY: POTENTIAL THERAPEUTIC TARGET IN HEPATIC FIBROSIS. Doctoral Dissertation, University of Pittsburgh.

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Abstract

Platelet-derived growth factor receptor (PDGFR) is a tyrosine kinase receptor that plays a role in cell survival, proliferation, and differentiation, and is involved in liver development, regeneration and chronic liver injury states such as hepatic fibrosis and cirrhosis. Hepatic stellate cells (HSCs) are the primary mediators of hepatic fibrosis through their activation from a quiescent state in response to the presence of pro-fibrotic growth factors such as PDGFs. Proliferation and migration are key outcomes of this transition, facilitating collagen deposition and migration of activated HSCs to sites of liver injury. We confirm the upregulation of PDGFRα in pericentral hepatocytes in CCl4-induced liver injury as well as HSCs/myofibroblasts in carbon tetrachloride (CCl4), bile duct ligation (BDL), and 0.1% 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced liver injury. After ruling out a significant contribution of hepatocyte PDGFRα in hepatic fibrosis using Alb-Cre and FoxA3-Cre Pdgfra-/- animals, we examine PDGFRα signaling in primary human HSCs (HHSteCs) in combination with human PDGFRα–specific inhibitory monoclonal antibody Olaratumab to test the hypothesis that PDGFRα signaling in HSCs promotes hepatic fibrosis. Olaratumab-mediated PDGFRα inhibition resulted in decreased HHSteC proliferation and motility, while lacking an effect on transcriptional expression of fibrosis-associated genes. Furthermore, Olaratumab reduced activation of downstream signaling effectors involved in proliferation and motility including Akt, mTOR, Erk1/2, FAK, and p38 MAPK suggesting that PDGFRα contributes to mitogenesis and actin reorganization through diverse downstream mediators. This evidence was corroborated with findings that HSC-specific Lrat-Cre Pdgfra-/- mice showed reduced CCl4-induced fibrosis after 4 weeks (early fibrosis) followed by reduced ALT/AST levels at 8 weeks (advanced fibrosis). This was accompanied by increased macrophage infiltration and increased TUNEL-positive HSCs/myofibroblasts concomitant with a decrease in TUNEL-positive hepatocytes, suggesting that PDGFRα loss in HSCs may promote injury resolution in advanced fibrosis by limiting HSC/myofibroblast survival. These findings support a distinct pro-fibrotic role of PDGFRα in HSCs during chronic liver injury in both mice and human primary cells and provides an important pre-clinical foundation for the future testing of therapeutic PDGFRα inhibition in hepatic fibrosis.


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Details

Item Type: University of Pittsburgh ETD
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Kikuchi, AlexanderATK25@pitt.eduATK25
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorMonga, Satdarshansmonga@pitt.edu
Committee ChairDeFrances, Mariedefrancesmc@upmc.edu
Committee MemberMichalopoulos, Georgemichalopoulosgk@upmc.edu
Committee MemberStolz, Donnadstolz@pitt.edu
Committee MemberXie, Wenwex6@pitt.edu
Date: 10 August 2017
Date Type: Publication
Defense Date: 14 July 2017
Approval Date: 10 August 2017
Submission Date: 9 August 2017
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Number of Pages: 151
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: PDGFR PDGFRalpha PDGF Hepatic fibrosis Cirrhosis Chronic liver injury Hepatic stellate cell (HSC) Myofibroblast Olaratumab HHSteC Growth factor Carbon Tetrachloride (CCl4) Bile duct ligation (BDL) 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) Akt Mammalian target of rapamycin (mTOR) Erk1/2 Focal adhesion kinase (FAK) p38 MAPK
Date Deposited: 10 Aug 2017 13:38
Last Modified: 10 Aug 2017 13:38
URI: http://d-scholarship.pitt.edu/id/eprint/33026

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