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ABSTRACT 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 αv integrin subunit because various αv-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

β3, β5 or β6 integrins or conditional loss of β8 integrins in HSCs did not. We also found that _Pdgfrb-_Cre effectively targeted myofibroblasts in multiple organs, and depletion of the αv

integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of αv-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 αv integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases. Access through your institution Buy or subscribe This is a

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MODEL FOR GENETIC MANIPULATION AND FATE-TRACING OF PDGFRΒ-EXPRESSING FIBROGENIC CELLS IN THE LIVER Article Open access 05 May 2023 AMPK STIMULATION INHIBITS YAP/TAZ SIGNALING TO AMELIORATE

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RGD-peptidomimetic agents S137 and S247. _Clin. Exp. Metastasis_ 21, 129–138 (2004). CAS  PubMed  Google Scholar  Download references ACKNOWLEDGEMENTS This work was supported by a Wellcome

Trust Intermediate Clinical Fellowship (ref. 085187) to N.C.H., National Institutes of Health grants HL102292, HL53949 and AI077439 (to D.S.), a University of California, San Francisco

(UCSF) Liver Center Tool and Technology grant (to N.C.H) and P30 DK026743 (UCSF Liver Center). We thank K. Thorn at the UCSF Nikon Imaging Center for assistance with image analysis. We also

thank C. Her, N. Wu, S. Huling, D. Rodrigues and R. Aucott for expert technical assistance. We also acknowledge the contribution of M. Singh (chemical synthesis of compounds CWHM 12 and CWHM

96), D. Tajfirouz, S. Freeman and M. Yates at Saint Louis University for technical assistance in conducting integrin functional assays to characterize compound activities. L. Reichardt

(UCSF) provided _Itgb8_flox/flox mice and R. Hynes (Massachusetts Institute of Technology) provided _Itgb3_−/− mice on 129/svJae background. S. Violette (Biogen Idec) provided antibody to

αvβ6 (human/mouse chimeric 2A1), W. Stallcup (Sanford-Burnham Medical Research Institute) provided antibody to PDGFR-β and H. Yagita (Juntendo University) provided antibody to αv integrin

(clone RMV-7). AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Medicine, Lung Biology Center, University of California, San Francisco, San Francisco, California, USA Neil C

Henderson, Yoshio Katamura, Marilyn M Giacomini, Juan D Rodriguez & Dean Sheppard * Medical Research Council Centre for Inflammation Research, The Queen's Medical Research

Institute, University of Edinburgh, Edinburgh, UK Neil C Henderson, Antonella Pellicoro & John P Iredale * Department of Pediatrics, University of California, San Francisco, San

Francisco, California, USA Thomas D Arnold * Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA Joseph H McCarty * Department of Immunology,

Genetics and Pathology, Uppsala University, Uppsala, Sweden Elisabeth Raschperger & Christer Betsholtz * Department of Medical Biochemistry and Biophysics, Karolinska Institutet,

Stockholm, Sweden Elisabeth Raschperger & Christer Betsholtz * Center for World Health and Medicine, Saint Louis University, Edward A. Doisy Research Center, St. Louis, Missouri, USA

Peter G Ruminski, David W Griggs & Michael J Prinsen * Department of Medicine, The Liver Center, University of California, San Francisco, San Francisco, California, USA Jacquelyn J Maher

* Department of Pediatrics, Program of Developmental Immunology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA Adam Lacy-Hulbert * Department of

Tissue Morphogenesis, Faculty of Medicine, Max Planck Institute for Molecular Biomedicine, University of Münster, Münster, Germany Ralf H Adams Authors * Neil C Henderson View author

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You can also search for this author inPubMed Google Scholar 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 _Itgav_flox/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 and N.C.H.,

J.P.I. and D.S. wrote the manuscript. CORRESPONDING AUTHORS Correspondence to Neil C Henderson or Dean Sheppard. ETHICS DECLARATIONS COMPETING INTERESTS P.G.R. and D.W.G. hold equity in

Antegrin Therapeutics, LLC. SUPPLEMENTARY INFORMATION SUPPLEMENTARY TEXT AND FIGURES Supplementary Figures 1–8 and Supplementary Methods (PDF 4801 kb) RIGHTS AND PERMISSIONS Reprints and

permissions ABOUT THIS ARTICLE CITE THIS ARTICLE Henderson, N., Arnold, T., Katamura, Y. _et al._ Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in

several organs. _Nat Med_ 19, 1617–1624 (2013). https://doi.org/10.1038/nm.3282 Download citation * Received: 03 April 2012 * Accepted: 17 June 2013 * Published: 10 November 2013 * Issue

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