title: Fibrin-mediated integrin signaling plays a critical role in hepatic regeneration after partial hepatectomy in mice.
abstract: Background. The regenerative capacity of the liver is critical for proper responses to injury. Fibrin extracellular matrix (ECM) deposition is a common response to insult and contributes to inflammatory liver injury. However, the role of this matrix in hepatic regeneration has not been determined.
  
  
  OBJECTIVE
  The purpose of this study was first to determine the role of fibrin ECM in hepatic regeneration followed by the role of the fibrin-binding αvβ3 integrin in mediating this effect.
  
  
  METHODS
  C57Bl/6J (WT) or PAI-1 knockout (KO) mice underwent 70% partial hepatectomy (PHx); plasma and histologic indices of regeneration were determined, as well as expression of key genes involved in hepatic regeneration.
  
  
  RESULTS
  PHx promoted transient fibrin deposition by activating coagulation and concomitantly decreasing fibrinolysis. Inhibiting fibrin deposition, either by blocking thrombin (hirudin) in WT mice or by knocking out PAI-1, was associated with a decrease in hepatocyte proliferation after PHx. This strongly suggested a role for fibrin ECM in liver regeneration. To investigate if αvβ3 integrin mediates this action, we tested the effects of the anti-αvβ3 cyclic peptide RGDfV in animals after PHx. As was observed with inhibition of fibrin deposition, competitive inhibition of αvβ3 integrin delayed regeneration after PHx, while not affecting fibrin deposition. These effects of RGDfV correlated with impaired angiogénesis and STAT3 signaling, as well as transient endothelial dysfunction. In conclusion, these data suggest that αvβ3 integrin plays an important role in coordinating hepatocyte division during liver regeneration after PHx via crosstalk with fibrin ECM.
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors: Juliane I
authors: JI
authors: Beier
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors: Luping
authors: L
authors: Guo
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors: Jeffrey D
authors: JD
authors: Ritzenthaler
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA;Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors: Swati
authors: S
authors: Joshi-Barve
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA;Department of Medicine, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors: Jesse
authors: J
authors: Roman
authors: Department of Pharmacology and Toxicology, University of Louisville Health Sciences Center, Louisville, KY, USA.
authors: Gavin E
authors: GE
authors: Arteel
mesh_terms: D000818:Animals; D001777:Blood Coagulation; D049109:Cell Proliferation / Q000187:drug effects; D005337:Fibrin / Q000378:metabolism*; D005342:Fibrinolysis; D005838:Genotype; D006498:Hepatectomy / Q000379:methods*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D039302:Integrin alphaVbeta3 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000601:surgery*; D008115:Liver Regeneration / Q000187:drug effects; D008297:Male; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010456:Peptides, Cyclic / Q000494:pharmacology; D010641:Phenotype; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors
chemical_list: D039302:Integrin alphaVbeta3; D010456:Peptides, Cyclic; D017395:Plasminogen Activator Inhibitor 1; C092113:cyclo(arginyl-glycyl-aspartyl-phenylalanyl-valyl); D005337:Fibrin