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

By N. Henderson, Thomas D. Arnold, Y. Katamura, Marilyn M. Giacomini, J. D. Rodriguez, J. McCarty, A. Pellicoro, Elisabeth Raschperger, C. Betsholtz, P. Ruminski and 7 more. Nature Medicine, 2013

619 citations recorded by the source corpus.

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.

Subfields: Hepatology, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/6c7cef752c951cddb5b612f5db2d029070e9a76c

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In Hepatology

1. L. Hammerich
2. M. Pinzani
3. M. Parola
4. E. Seki
5. F. Tacke
6. Robert F. Schwabe
7. Steven Dooley
8. S. Friedman

In Molecular Biology

1. D. Sheppard
2. F. Tacke
3. Kevin K. Kim
4. Robert F. Schwabe
5. H. Chapman
6. L. Hammerich

In Pulmonary and Respiratory Medicine

1. D. Sheppard
2. F. Tacke

Citations in the corpus

• Hepatic inflammatory responses in liver fibrosis (2023, positive): “Integrins containing αV subunits can induce a transition of latent to active TGFβ in the ECM, and deletion of this subunit protected mice from fibrosis development in several organs 170 .”
• Hepatic Inflammation and Fibrosis: Functional Links and Key Pathways (2015, background): “TGF-b requires processing to become bioactive, which can be mediated by MMPs, pH, trombospondin-1, reactive oxygen species (ROS), or av integrins.(64,65) TGF-b and pro-inflammatory signaling pathways interact at multiple levels, as HEPATOLOGY, Vol.”
• Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis (2014, critical): “However, shortly after this report, another group demonstrated that PDGFRb+ cells do indeed contribute to the myofibroblast pool in kidney, lung, and heart fibrosis (Henderson et al., 2013).”
• Liver fibrosis: Pathophysiology, pathogenetic targets and clinical issues. (2019, background): “HSC activation can also relies on the contact with altered ECM (shifting from basal-like towards fibrillary ECM) through integrin-mediated signals (Henderson et al., 2013) or to favor HSC activation dependent on several peptide mediators (PDGF, FGF, HGF, VEGF) that remain entrapped in the altered EC”
• TGF-β in Hepatic Stellate Cell Activation and Liver Fibrogenesis—Updated 2019 (2019, background): “Other approaches inhibited TGF-β signaling indirectly through targeting LOXL or integrins, and therewith reducing release of active TGF-β from its ECM deposited latent form [108,129,263].”
• TGF-β1 Signaling and Tissue Fibrosis. (2018, background): “Continuous subcutaneous administration of this inhibitor during the late phases of bleomycin-induced pulmonary fibrosis or carbon tetrachloride (CCl4)-induced hepatic fibrosis results in protection that is similar to that by a small molecule inhibitor of all av integrins (Henderson et al. 2013).”