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Selective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs

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

Journal Title: Nature medicine 2013, Vol.19 (12)
Main Author: Henderson, Neil C Neil C
Other Authors: Arnold, Thomas D Thomas D , Katamura, Yoshio Yoshio , Giacomini, Marilyn M Marilyn M , Rodriguez, Juan D Juan D , McCarty, Joseph H Joseph H , Pellicoro, Antonella Antonella , Raschperger, Elisabeth Elisabeth , Betsholtz, Christer Christer , Ruminski, Peter G Peter G , Griggs, David W David W , Prinsen, Michael J Michael J , Maher, Jacquelyn J Jacquelyn J , Iredale, John P John P , Lacy-Hulbert, Adam Adam , Adams, Ralf H Ralf H , Sheppard, Dean Dean
Format: Electronic Article Electronic Article
Language: English
ID: ISSN: 1078-8956
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title: Selective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs
format: Article
creator:
  • Henderson, Neil C Neil C
  • Arnold, Thomas D Thomas D
  • Katamura, Yoshio Yoshio
  • Giacomini, Marilyn M Marilyn M
  • Rodriguez, Juan D Juan D
  • McCarty, Joseph H Joseph H
  • Pellicoro, Antonella Antonella
  • Raschperger, Elisabeth Elisabeth
  • Betsholtz, Christer Christer
  • Ruminski, Peter G Peter G
  • Griggs, David W David W
  • Prinsen, Michael J Michael J
  • Maher, Jacquelyn J Jacquelyn J
  • Iredale, John P John P
  • Lacy-Hulbert, Adam Adam
  • Adams, Ralf H Ralf H
  • Sheppard, Dean Dean
ispartof: Nature medicine, 2013, Vol.19 (12)
description: Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb -Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl 4 -induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb -Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv 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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titleSelective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs
creatorHenderson, Neil C Neil C ; Arnold, Thomas D Thomas D ; Katamura, Yoshio Yoshio ; Giacomini, Marilyn M Marilyn M ; Rodriguez, Juan D Juan D ; McCarty, Joseph H Joseph H ; Pellicoro, Antonella Antonella ; Raschperger, Elisabeth Elisabeth ; Betsholtz, Christer Christer ; Ruminski, Peter G Peter G ; Griggs, David W David W ; Prinsen, Michael J Michael J ; Maher, Jacquelyn J Jacquelyn J ; Iredale, John P John P ; Lacy-Hulbert, Adam Adam ; Adams, Ralf H Ralf H ; Sheppard, Dean Dean
creatorcontribHenderson, Neil C Neil C ; Arnold, Thomas D Thomas D ; Katamura, Yoshio Yoshio ; Giacomini, Marilyn M Marilyn M ; Rodriguez, Juan D Juan D ; McCarty, Joseph H Joseph H ; Pellicoro, Antonella Antonella ; Raschperger, Elisabeth Elisabeth ; Betsholtz, Christer Christer ; Ruminski, Peter G Peter G ; Griggs, David W David W ; Prinsen, Michael J Michael J ; Maher, Jacquelyn J Jacquelyn J ; Iredale, John P John P ; Lacy-Hulbert, Adam Adam ; Adams, Ralf H Ralf H ; Sheppard, Dean Dean
descriptionMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb -Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl 4 -induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb -Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
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titleSelective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs
authorHenderson, Neil C Neil C ; Arnold, Thomas D Thomas D ; Katamura, Yoshio Yoshio ; Giacomini, Marilyn M Marilyn M ; Rodriguez, Juan D Juan D ; McCarty, Joseph H Joseph H ; Pellicoro, Antonella Antonella ; Raschperger, Elisabeth Elisabeth ; Betsholtz, Christer Christer ; Ruminski, Peter G Peter G ; Griggs, David W David W ; Prinsen, Michael J Michael J ; Maher, Jacquelyn J Jacquelyn J ; Iredale, John P John P ; Lacy-Hulbert, Adam Adam ; Adams, Ralf H Ralf H ; Sheppard, Dean Dean
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8Betsholtz, Christer Christer
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6Pellicoro, Antonella Antonella
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atitleSelective αv integrin depletion identifies a core, targetable molecular pathway that regulates fibrosis across solid organs
jtitleNature medicine
date2013-11-10
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issn1078-8956
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notesAuthor contributions N.C.H. and D.S. conceived and designed the project. N.C.H. performed the experiments with assistance from T.D.A., Y.K., M.M.G., J.D.R. and A.P..; J.H.M. contributed reagents; P.G.R., D.W.G. and M.J.P. designed and synthesized the small molecule αv integrin inhibitor (CWHM 12) and performed the ligand binding studies to characterize the in vitro potency of CWHM 12; J.J.M. and J.P.I. contributed reagents and provided substantial intellectual contribution; E.R. and C.B. contributed Pdgfrb-BAC-eGFP knock-in reporter mice; A.L.H. contributed itgavflox/flox mice; R.H.A. contributed Pdgfrb-Cre mice; N.C.H., T.D.A., Y.K., M.M.G. and D.S. analyzed data; N.C.H., J.P.I. and D.S. wrote the manuscript.
abstractMyofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not existed. We report that Pdgfrb -Cre inactivates genes in murine HSCs with high efficiency. We used this system to delete the αv integrin subunit because of the suggested role of multiple αv integrins as central mediators of fibrosis in multiple organs. Depletion of the αv integrin subunit in HSCs protected mice from CCl 4 -induced hepatic fibrosis, whereas global loss of αvβ3, αvβ5 or αvβ6 or conditional loss of αvβ8 on HSCs did not. Pdgfrb -Cre effectively targeted myofibroblasts in multiple organs, and depletion of αv integrins using this system was also protective in models of pulmonary and renal fibrosis. Critically, pharmacological blockade of αv integrins by a novel small molecule (CWHM 12) attenuated both liver and lung fibrosis, even when administered after fibrosis was established. These data identify a core pathway that regulates fibrosis, and suggest that pharmacological targeting of all αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.
pmid24216753
doi10.1038/nm.3282
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