Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs
Open accessAbstract
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 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 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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Small molecule inhibition and antibody blockade of integrin αvβ6 have both been shown to effectively attenuate biliary and non-biliary fibrogenesis with reduced proliferation of cholangiocyte-like progenitor cells and attenuated TGFβ1 activation.
“Small molecule inhibition and antibody blockade of integrin αvβ6 have both been shown to effectively attenuate biliary and non-biliary fibrogenesis with reduced proliferation of cholangiocyte-like progenitor cells and attenuated TGFβ1 activation.59,60”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [59]
Quiescent HSCs differentiate into myofibroblasts in response to growth factors such as PDGF from macrophages, CTGF from mesenchyme/endothelial cells, VEGF and TGFβ1.
“In response to growth factors such as PDGF from macrophages, connective tissue growth factor (CTGF) from mesenchyme/endothelial cells, VEGF and TGFβ1, quiescent HSCs differentiate into myofibroblasts.54,59”
From Understanding the cellular interactome of non-alcoholic fatty liver disease (2022) · cites this paper as [59]
Preclinical models support targeting αv integrins in NASH fibrosis.
“Preclinical models support this approach in NASH fibrosis.115”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [115]
Blocking TGF-β activation by targeting αv-containing integrins at the cell surface is a promising approach.
“However, inhibiting the activation of TGF-β by targeting the αv-containing subset of integrins at the cell surface (e.g., integrins αvb1, αvβ3, αvβ5, αvβ6 and αvβ8) is promising.”
From An integrated view of anti-inflammatory and antifibrotic targets for the treatment of NASH (2023) · cites this paper as [115]
IL-17A signaling has a confirmed role in fibrosis development in multiple tissues, based on IL-17A- and IL-17RA-deficient mice and neutralizing monoclonal antibodies.
“Experiments with IL-17A- and IL-17RA-deficient mice, as well as therapeutic studies with IL-17A neutralizing monoclonal antibodies confirmed a role for IL-17A signaling in the development of fibrosis in multiple tissues110–112,116–118”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [117]
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- Authors
- Henderson, N. C., Arnold, T. D., Katamura, Y., Giacomini, M. M., Rodriguez, J. D., McCarty, J. H., Pellicoro, A., Raschperger, E., Betsholtz, C., Ruminski, P. G., Griggs, D. W., Prinsen, M. J., Maher, J. J., Iredale, J. P., Lacy-Hulbert, A., Adams, R. H., & Sheppard, D.
- Affiliations
- University of California, San Francisco (US)
- The University of Texas MD Anderson Cancer Center (US)
- Centre for Inflammation Research (GB)
- Uppsala University (SE)
- Saint Louis University (US)
- University of Münster (DE)
- Corresponding author
- Henderson, Neil C
- Sheppard, Dean
- ORCID
- Venue
- Nature Medicine
- Published
- 2013-11-10
- Volume
- 19
- Issue
- 12
- Pages
- 1617-1624
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC3855865
- OpenAlex
- W2105231460
- Cited by
- 866
- References
- 48
- Citations by year
- 2026: 52 · 2025: 55 · 2024: 63 · 2023: 70 · 2022: 63 · 2021: 98 · 2020: 62 · 2019: 65 · 2018: 75 · 2017: 78 · 2016: 64 · 2015: 63 · 2014: 50 · 2013: 5 · 2012: 1
- FWCI
- 34.06
- Type
- journal article
- Language
- en
- Open access
- Licence
- other-oa
- www.springer.com/tdm (tdm)
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Edinburgh Research Explorer (University of Edinburgh) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (085187, P30 DK026743)
- Saint Louis University
- National Institutes of Health (HL53949, AI077439)
- University of California, San Francisco (P30DK026743)
- Medical Research Council (MR/J010766/1)
- National Heart, Lung, and Blood Institute (P01HL108794, R37HL053949, HL53949, R01HL102292, HL102292, R01HL053949)
- National Institute of Allergy and Infectious Diseases (AI077439, U19AI077439)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK026743, R01DK093695)
- National Institute of Neurological Disorders and Stroke (R01NS078402)
- Liver Center, University of California, San Francisco (P30 DK026743)
- Topics
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Interstitial Lung Diseases and Idiopathic Pulmonary Fibrosis
- Keywords
- ITGAV, fibrosis, hepatic stellate cells, myofibroblasts, liver fibrosis, pulmonary fibrosis, renal fibrosis, integrin blockade, extracellular matrix
- MeSH terms
- Animals, Cells, Cultured, Drug Evaluation, Preclinical, Female, Fibrosis, Kidney, Kidney Diseases, Liver Cirrhosis, Male, Mice, Inbred C57BL, Mice, Transgenic, Pulmonary Fibrosis, Signal Transduction, Gene Targeting, Integrin alphaV, Mice, Myofibroblasts
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