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Targeting of [alpha]v integrin identifies a core molecular pathway that regulates fibrosis in several organs

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed.... Full description

Journal Title: Nature medicine 2013, Vol.19 (12), p.1617
Main Author: Neil C Henderson
Other Authors: Thomas D Arnold , Yoshio Katamura , Marilyn M Giacomini , Juan D Rodriguez , Joseph H Mccarty , Antonella Pellicoro , Elisabeth Raschperger , Christer Betsholtz , Peter G Ruminski , David W Griggs , Michael J Prinsen , Jacquelyn J Maher , John P Iredale , Adam Lacy-hulbert , Ralf H Adams , Dean Sheppard
Format: Electronic Article Electronic Article
Language: English
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Publisher: New York: Nature Publishing Group
ID: ISSN: 1078-8956
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title: Targeting of [alpha]v integrin identifies a core molecular pathway that regulates fibrosis in several organs
format: Article
creator:
  • Neil C Henderson
  • Thomas D Arnold
  • Yoshio Katamura
  • Marilyn M Giacomini
  • Juan D Rodriguez
  • Joseph H Mccarty
  • Antonella Pellicoro
  • Elisabeth Raschperger
  • Christer Betsholtz
  • Peter G Ruminski
  • David W Griggs
  • Michael J Prinsen
  • Jacquelyn J Maher
  • John P Iredale
  • Adam Lacy-hulbert
  • Ralf H Adams
  • Dean Sheppard
subjects:
  • Biomedical research
  • Liver diseases
  • Lung diseases
  • Pharmaceutical sciences
  • Studies
ispartof: Nature medicine, 2013, Vol.19 (12), p.1617
description: Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of [beta], [beta] or [beta] integrins or conditional loss of [beta] integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
language: eng
source:
identifier: ISSN: 1078-8956
fulltext: no_fulltext
issn:
  • 1078-8956
  • 1546-170X
url: Link


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titleTargeting of [alpha]v integrin identifies a core molecular pathway that regulates fibrosis in several organs
creatorNeil C Henderson ; Thomas D Arnold ; Yoshio Katamura ; Marilyn M Giacomini ; Juan D Rodriguez ; Joseph H Mccarty ; Antonella Pellicoro ; Elisabeth Raschperger ; Christer Betsholtz ; Peter G Ruminski ; David W Griggs ; Michael J Prinsen ; Jacquelyn J Maher ; John P Iredale ; Adam Lacy-hulbert ; Ralf H Adams ; Dean Sheppard
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descriptionMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of [beta], [beta] or [beta] integrins or conditional loss of [beta] integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
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abstractMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of [beta], [beta] or [beta] integrins or conditional loss of [beta] integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
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doi10.1038/nm.3282