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CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism

IntroductionCD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.ObjectiveTo determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.DesignCD248 expressi... Full description

Journal Title: Gut 2016, Vol.65 (7), p.1175-1185
Main Author: Wilhelm, Annika
Other Authors: Aldridge, Victoria , Haldar, Debashis , Naylor, Amy J , Weston, Christopher J , Hedegaard, Ditte , Garg, Abhilok , Fear, Janine , Reynolds, Gary M , Croft, Adam P , Henderson, Neil C , Buckley, Christopher D , Newsome, Philip N
Format: Electronic Article Electronic Article
Language: English
Subjects:
Publisher: England: British Medical Association
ID: ISSN: 0017-5749
Link: https://www.ncbi.nlm.nih.gov/pubmed/26078290
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recordid: cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_4941145
title: CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism
format: Article
creator:
  • Wilhelm, Annika
  • Aldridge, Victoria
  • Haldar, Debashis
  • Naylor, Amy J
  • Weston, Christopher J
  • Hedegaard, Ditte
  • Garg, Abhilok
  • Fear, Janine
  • Reynolds, Gary M
  • Croft, Adam P
  • Henderson, Neil C
  • Buckley, Christopher D
  • Newsome, Philip N
subjects:
  • 1506
  • Actins - analysis
  • Angiogenesis Inducing Agents - pharmacology
  • Animals
  • Antigens, CD - analysis
  • Antigens, CD - genetics
  • Antigens, CD - metabolism
  • Antigens, Neoplasm - analysis
  • Antigens, Neoplasm - genetics
  • Antigens, Neoplasm - metabolism
  • Becaplermin
  • Carbon Tetrachloride
  • Care and treatment
  • Cell Proliferation - drug effects
  • Cell Proliferation - genetics
  • Cells, Cultured
  • Chemical and Drug Induced Liver Injury - metabolism
  • Chronic Disease
  • Collagen - metabolism
  • Desmin - analysis
  • Dosage and administration
  • FIBROSIS
  • Gene Expression
  • HEPATIC STELLATE CELL
  • Hepatic Stellate Cells - chemistry
  • Hepatic Stellate Cells - physiology
  • Hepatology
  • Humans
  • Inflammation - genetics
  • Liver - chemistry
  • Liver - pathology
  • Liver Cirrhosis - chemically induced
  • Liver Cirrhosis - metabolism
  • Liver diseases
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • MYOFIBROBLASTS
  • Neovascularization, Pathologic - genetics
  • Platelet-Derived Growth Factor - metabolism
  • Proto-Oncogene Proteins c-fos - metabolism
  • Proto-Oncogene Proteins c-sis - pharmacology
  • Receptor, Platelet-Derived Growth Factor alpha - metabolism
  • Receptor, Platelet-Derived Growth Factor beta - metabolism
  • RNA, Messenger - metabolism
  • Signal Transduction - genetics
  • Transforming Growth Factor beta - genetics
  • Vimentin - analysis
ispartof: Gut, 2016, Vol.65 (7), p.1175-1185
description: IntroductionCD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.ObjectiveTo determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.DesignCD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248−/− and wild-type controls with carbon tetrachloride (CCl4) treatment.ResultsExpression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248−/− mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248−/− mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248−/− HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248−/− HSC was confirmed by significantly reduced c-fos expression in CD248−/− HSC compared with wild-type HSC.ConclusionsOur data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury.
language: eng
source:
identifier: ISSN: 0017-5749
fulltext: no_fulltext
issn:
  • 0017-5749
  • 1468-3288
url: Link


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titleCD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism
creatorWilhelm, Annika ; Aldridge, Victoria ; Haldar, Debashis ; Naylor, Amy J ; Weston, Christopher J ; Hedegaard, Ditte ; Garg, Abhilok ; Fear, Janine ; Reynolds, Gary M ; Croft, Adam P ; Henderson, Neil C ; Buckley, Christopher D ; Newsome, Philip N
creatorcontribWilhelm, Annika ; Aldridge, Victoria ; Haldar, Debashis ; Naylor, Amy J ; Weston, Christopher J ; Hedegaard, Ditte ; Garg, Abhilok ; Fear, Janine ; Reynolds, Gary M ; Croft, Adam P ; Henderson, Neil C ; Buckley, Christopher D ; Newsome, Philip N
descriptionIntroductionCD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.ObjectiveTo determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.DesignCD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248−/− and wild-type controls with carbon tetrachloride (CCl4) treatment.ResultsExpression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248−/− mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248−/− mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248−/− HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248−/− HSC was confirmed by significantly reduced c-fos expression in CD248−/− HSC compared with wild-type HSC.ConclusionsOur data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury.
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languageeng
publisherEngland: British Medical Association
subject1506 ; Actins - analysis ; Angiogenesis Inducing Agents - pharmacology ; Animals ; Antigens, CD - analysis ; Antigens, CD - genetics ; Antigens, CD - metabolism ; Antigens, Neoplasm - analysis ; Antigens, Neoplasm - genetics ; Antigens, Neoplasm - metabolism ; Becaplermin ; Carbon Tetrachloride ; Care and treatment ; Cell Proliferation - drug effects ; Cell Proliferation - genetics ; Cells, Cultured ; Chemical and Drug Induced Liver Injury - metabolism ; Chronic Disease ; Collagen - metabolism ; Desmin - analysis ; Dosage and administration ; FIBROSIS ; Gene Expression ; HEPATIC STELLATE CELL ; Hepatic Stellate Cells - chemistry ; Hepatic Stellate Cells - physiology ; Hepatology ; Humans ; Inflammation - genetics ; Liver - chemistry ; Liver - pathology ; Liver Cirrhosis - chemically induced ; Liver Cirrhosis - metabolism ; Liver diseases ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; MYOFIBROBLASTS ; Neovascularization, Pathologic - genetics ; Platelet-Derived Growth Factor - metabolism ; Proto-Oncogene Proteins c-fos - metabolism ; Proto-Oncogene Proteins c-sis - pharmacology ; Receptor, Platelet-Derived Growth Factor alpha - metabolism ; Receptor, Platelet-Derived Growth Factor beta - metabolism ; RNA, Messenger - metabolism ; Signal Transduction - genetics ; Transforming Growth Factor beta - genetics ; Vimentin - analysis
ispartofGut, 2016, Vol.65 (7), p.1175-1185
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0Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing
1Copyright: 2016 Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing
2Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/ 2016
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1Aldridge, Victoria
2Haldar, Debashis
3Naylor, Amy J
4Weston, Christopher J
5Hedegaard, Ditte
6Garg, Abhilok
7Fear, Janine
8Reynolds, Gary M
9Croft, Adam P
10Henderson, Neil C
11Buckley, Christopher D
12Newsome, Philip N
title
0CD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism
1Gut
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descriptionIntroductionCD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.ObjectiveTo determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.DesignCD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248−/− and wild-type controls with carbon tetrachloride (CCl4) treatment.ResultsExpression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248−/− mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248−/− mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248−/− HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248−/− HSC was confirmed by significantly reduced c-fos expression in CD248−/− HSC compared with wild-type HSC.ConclusionsOur data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury.
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01506
1Actins - analysis
2Angiogenesis Inducing Agents - pharmacology
3Animals
4Antigens, CD - analysis
5Antigens, CD - genetics
6Antigens, CD - metabolism
7Antigens, Neoplasm - analysis
8Antigens, Neoplasm - genetics
9Antigens, Neoplasm - metabolism
10Becaplermin
11Carbon Tetrachloride
12Care and treatment
13Cell Proliferation - drug effects
14Cell Proliferation - genetics
15Cells, Cultured
16Chemical and Drug Induced Liver Injury - metabolism
17Chronic Disease
18Collagen - metabolism
19Desmin - analysis
20Dosage and administration
21FIBROSIS
22Gene Expression
23HEPATIC STELLATE CELL
24Hepatic Stellate Cells - chemistry
25Hepatic Stellate Cells - physiology
26Hepatology
27Humans
28Inflammation - genetics
29Liver - chemistry
30Liver - pathology
31Liver Cirrhosis - chemically induced
32Liver Cirrhosis - metabolism
33Liver diseases
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35Mice, Inbred C57BL
36Mice, Knockout
37MYOFIBROBLASTS
38Neovascularization, Pathologic - genetics
39Platelet-Derived Growth Factor - metabolism
40Proto-Oncogene Proteins c-fos - metabolism
41Proto-Oncogene Proteins c-sis - pharmacology
42Receptor, Platelet-Derived Growth Factor alpha - metabolism
43Receptor, Platelet-Derived Growth Factor beta - metabolism
44RNA, Messenger - metabolism
45Signal Transduction - genetics
46Transforming Growth Factor beta - genetics
47Vimentin - analysis
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4Weston, Christopher J
5Hedegaard, Ditte
6Garg, Abhilok
7Fear, Janine
8Reynolds, Gary M
9Croft, Adam P
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titleCD248/endosialin critically regulates hepatic stellate cell proliferation during chronic liver injury via a PDGF-regulated mechanism
authorWilhelm, Annika ; Aldridge, Victoria ; Haldar, Debashis ; Naylor, Amy J ; Weston, Christopher J ; Hedegaard, Ditte ; Garg, Abhilok ; Fear, Janine ; Reynolds, Gary M ; Croft, Adam P ; Henderson, Neil C ; Buckley, Christopher D ; Newsome, Philip N
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01506
1Actins - analysis
2Angiogenesis Inducing Agents - pharmacology
3Animals
4Antigens, CD - analysis
5Antigens, CD - genetics
6Antigens, CD - metabolism
7Antigens, Neoplasm - analysis
8Antigens, Neoplasm - genetics
9Antigens, Neoplasm - metabolism
10Becaplermin
11Carbon Tetrachloride
12Care and treatment
13Cell Proliferation - drug effects
14Cell Proliferation - genetics
15Cells, Cultured
16Chemical and Drug Induced Liver Injury - metabolism
17Chronic Disease
18Collagen - metabolism
19Desmin - analysis
20Dosage and administration
21FIBROSIS
22Gene Expression
23HEPATIC STELLATE CELL
24Hepatic Stellate Cells - chemistry
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27Humans
28Inflammation - genetics
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31Liver Cirrhosis - chemically induced
32Liver Cirrhosis - metabolism
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35Mice, Inbred C57BL
36Mice, Knockout
37MYOFIBROBLASTS
38Neovascularization, Pathologic - genetics
39Platelet-Derived Growth Factor - metabolism
40Proto-Oncogene Proteins c-fos - metabolism
41Proto-Oncogene Proteins c-sis - pharmacology
42Receptor, Platelet-Derived Growth Factor alpha - metabolism
43Receptor, Platelet-Derived Growth Factor beta - metabolism
44RNA, Messenger - metabolism
45Signal Transduction - genetics
46Transforming Growth Factor beta - genetics
47Vimentin - analysis
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1Aldridge, Victoria
2Haldar, Debashis
3Naylor, Amy J
4Weston, Christopher J
5Hedegaard, Ditte
6Garg, Abhilok
7Fear, Janine
8Reynolds, Gary M
9Croft, Adam P
10Henderson, Neil C
11Buckley, Christopher D
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8Reynolds, Gary M
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abstractIntroductionCD248 (endosialin) is a stromal cell marker expressed on fibroblasts and pericytes. During liver injury, myofibroblasts are the main source of fibrotic matrix.ObjectiveTo determine the role of CD248 in the development of liver fibrosis in the rodent and human setting.DesignCD248 expression was studied by immunostaining and quantitative PCR in both normal and diseased human and murine liver tissue and isolated hepatic stellate cells (HSCs). Hepatic fibrosis was induced in CD248−/− and wild-type controls with carbon tetrachloride (CCl4) treatment.ResultsExpression of CD248 was seen in normal liver of humans and mice but was significantly increased in liver injury using both immunostaining and gene expression assays. CD248 was co-expressed with a range of fibroblast/HSC markers including desmin, vimentin and α-smooth muscle actin (α-SMA) in murine and human liver sections. CD248 expression was restricted to isolated primary murine and human HSC. Collagen deposition and α-SMA expression, but not inflammation and neoangiogenesis, was reduced in CD248−/− mice compared with wild-type mice after CCl4 treatment. Isolated HSC from wild-type and CD248−/− mice expressed platelet-derived growth factor receptor α (PDGFR-α) and PDGFR-β at similar levels. As expected, PDGF-BB stimulation induced proliferation of wild-type HSC, whereas CD248−/− HSC did not demonstrate a proliferative response to PDGF-BB. Abrogated PDGF signalling in CD248−/− HSC was confirmed by significantly reduced c-fos expression in CD248−/− HSC compared with wild-type HSC.ConclusionsOur data show that deletion of CD248 reduces susceptibility to liver fibrosis via an effect on PDGF signalling, making it an attractive clinical target for the treatment of liver injury.
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pmid26078290
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