The MET Receptor Tyrosine Kinase Confers Repair of Murine Pancreatic Acinar Cells following Acute and Chronic Injury

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Abstract

Acinar cells represent the primary target in necroinflammatory diseases of the pancreas, including pancreatitis. The signaling pathways guiding acinar cell repair and regeneration following injury remain poorly understood. The purpose of this study was to determine the importance of Hepatocyte Growth Factor Receptor/MET signaling as an intrinsic repair mechanism for acinar cells following acute damage and chronic alcohol-associated injury. Here, we generated mice with targeted deletion of MET in adult acinar cells (MET ^-/-). Acute and repetitive pancreatic injury was induced in MET ^-/- and control mice with cerulein, and chronic injury by feeding mice Lieber-DeCarli diets containing alcohol with or without enhancement of repetitive pancreatic injury. We examined the exocrine pancreas of these mice histologically for acinar death, edema, inflammation and collagen deposition and changes in the transcriptional program. We show that MET expression is relatively low in normal adult pancreas. However, MET levels were elevated in ductal and acinar cells in human pancreatitis specimens, consistent with a role for MET in an adaptive repair mechanism. We report that genetic deletion of MET in adult murine acinar cells was linked to increased acinar cell death, chronic inflammation and delayed recovery (regeneration) of pancreatic exocrine tissue. Notably, increased pancreatic collagen deposition was detected in MET knockout mice following repetitive injury as well alcohol-associated injury. Finally, we identified specific alterations of the pancreatic transcriptome associated with MET signaling during injury, involved in tissue repair, inflammation and endoplasmic reticulum stress. Together, these data demonstrate the importance of MET signaling for acinar repair and regeneration, a novel finding that could attenuate the symptomology of pancreatic injury.

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CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum.

H Zinszner, M Kuroda, X. Wang … (1998)

Cellular stress, particularly in response to toxic and metabolic insults that perturb function of the endoplasmic reticulum (ER stress), is a powerful inducer of the transcription factor CHOP. The role of CHOP in the response of cells to injury associated with ER stress was examined in a murine deficiency model obtained by homologous recombination at the chop gene. Compared with the wild type, mouse embryonic fibroblasts (MEFs) derived from chop -/- animals exhibited significantly less programmed cell death when challenged with agents that perturb ER function. A similar deficit in programmed cells death in response to ER stress was also observed in MEFs that lack CHOP's major dimerization partner, C/EBPbeta, implicating the CHOP-C/EBP pathway in programmed cell death. An animal model for studying the effects of chop on the response to ER stress was developed. It entailed exposing mice with defined chop genotypes to a single sublethal intraperitoneal injection of tunicamycin and resulted in a severe illness characterized by transient renal insufficiency. In chop +/+ and chop +/- mice this was associated with the early expression of CHOP in the proximal tubules followed by the development of a histological picture similar to the human condition known as acute tubular necrosis, a process that resolved by cellular regeneration. In the chop -/- animals, in spite of the severe impairment in renal function, evidence of cellular death in the kidney was reduced compared with the wild type. The proximal tubule epithelium of chop -/- animals exhibited fourfold lower levels of TUNEL-positive cells (a marker for programmed cell death), and significantly less evidence for subsequent regeneration. CHOP therefore has a role in the induction of cell death under conditions associated with malfunction of the ER and may also have a role in cellular regeneration under such circumstances.

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Hepatocyte growth factor/c-met signaling pathway is required for efficient liver regeneration and repair.

Chang-Goo Huh, Valentina Factor, Aránzazu Sánchez … (2004)

Hepatocyte growth factor/scatter factor c-met signaling pathway is of central importance during development as well as in tumorigenesis. Because homozygous null mice for either hgf/sf or c-met die in utero, we used Cre/loxP-mediated gene targeting to investigate the function of c-met specifically in the adult liver. Loss of c-met appeared not to be detrimental to hepatocyte function under physiological conditions. Nonetheless, the adaptive responses of the liver to injury were dramatically affected. Mice lacking c-met gene in hepatocytes were hypersensitive to Fas-induced apoptosis. When injected with a low dose of anti-Fas antibody, the majority of these mice died from massive apoptosis and hemorrhagic necrosis, whereas all wild-type mice survived with signs of minor injury. After a challenge with a single necrogenic dose of CCl4, c-met conditional knockout mice exhibited impaired recovery from centrolobular lesions rather than a deficit in hepatocyte proliferation. The delayed healing was associated with a persistent inflammatory reaction, over-production of osteopontin, early and prominent dystrophic calcification, and impaired hepatocyte scattering/migration into diseased areas. These studies provide direct genetic evidence in support of the critical role of c-met in efficient liver regeneration and suggest that disruption of c-met affects primarily hepatocyte survival and tissue remodeling.

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Models of acute and chronic pancreatitis.

Fred Gorelick, Markus M. Lerch (2013)

Animal models of acute and chronic pancreatitis have been created to examine mechanisms of pathogenesis, test therapeutic interventions, and study the influence of inflammation on the development of pancreatic cancer. In vitro models can be used to study early stage, short-term processes that involve acinar cell responses. Rodent models reproducibly develop mild or severe disease. One of the most commonly used pancreatitis models is created by administration of supraphysiologic concentrations of caerulein, an ortholog of cholecystokinin. Induction of chronic pancreatitis with factors thought to have a role in human disease, such as combinations of lipopolysaccharide and chronic ethanol feeding, might be relevant to human disease. Models of autoimmune chronic pancreatitis have also been developed. Most models, particularly of chronic pancreatitis, require further characterization to determine which features of human disease they include. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

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Author and article information

Contributors

Zoltán Rakonczay Jr.: Role: Editor

Journal

Journal ID (nlm-ta): PLoS One

Journal ID (iso-abbrev): PLoS ONE

Journal ID (publisher-id): plos

Journal ID (pmc): plosone

Title: PLoS ONE

Publisher: Public Library of Science (San Francisco, CA USA )

ISSN (Electronic): 1932-6203

Publication date (Electronic): 31 October 2016

Publication date Collection: 2016

Volume: 11

Issue: 10

Electronic Location Identifier: e0165485

Affiliations

[1 ]Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX, United States of America

[2 ]Department of Pathology, University of Texas Medical Branch, Galveston, TX, United States of America

[3 ]Department of Pharmacology and Toxicology, University of Texas Medical Branch, Galveston, TX, United States of America

[4 ]Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, United States of America

[5 ]Division of Gastroenterology, Hepatology and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, United States of America

[6 ]Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, United States of America

University of Szeged, HUNGARY

Author notes

Competing Interests: The authors have declared that no competing interests exist

Conceptualization: IG CJE LAE.
Data curation: IG DJ LAE.
Formal analysis: IG DJ PJB BK XT LS SQ.
Funding acquisition: DJ CJE CDL LAE.
Investigation: IG DJ BK KPdC XT LAE.
Methodology: IG DJ DC ZC-M ADJ CDL BK XT LAE.
Project administration: LAE.
Resources: CJE ZC-M CDL SQ LAE.
Supervision: CJE LAE.
Validation: IG DJ KPdC.
Visualization: IG LAE.
Writing – original draft: IG CJE LS LAE.
Writing – review & editing: IG ZC-M CJE CDL LS LAE.

* E-mail: lisa.elferink@ 123456utmb.edu

Article

Publisher ID: PONE-D-16-27379

DOI: 10.1371/journal.pone.0165485

PMC ID: 5087859

PubMed ID: 27798657

SO-VID: 11ad50dd-9134-46f1-bef0-343a7a20a996

License:

This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

History

Date received : 8 July 2016

Date accepted : 12 October 2016

Page count

Figures: 7, Tables: 0, Pages: 20

Funding

Funded by: funder-id http://dx.doi.org/10.13039/100000027, National Institute on Alcohol Abuse and Alcoholism;

Award ID: 1R21AA0249001

Award Recipient : Lisa A. Elferink