title: Urokinase plasminogen receptor and the fibrinolytic complex play a role in nerve repair after nerve crush in mice, and in human neuropathies.
abstract: Remodeling of extracellular matrix (ECM) is a critical step in peripheral nerve regeneration. In fact, in human neuropathies, endoneurial ECM enriched in fibrin and vitronectin associates with poor regeneration and worse clinical prognosis. Accordingly in animal models, modification of the fibrinolytic complex activity has profound effects on nerve regeneration: high fibrinolytic activity and low levels of fibrin correlate with better nerve regeneration. The urokinase plasminogen receptor (uPAR) is a major component of the fibrinolytic complex, and binding to urokinase plasminogen activator (uPA) promotes fibrinolysis and cell movement. uPAR is expressed in peripheral nerves, however, little is known on its potential function on nerve development and regeneration. Thus, we investigated uPAR null mice and observed that uPAR is dispensable for nerve development, whereas, loss of uPAR affects nerve regeneration. uPAR null mice showed reduced nerve repair after sciatic nerve crush. This was a consequence of reduced fibrinolytic activity and increased deposition of endoneurial fibrin and vitronectin. Exogenous fibrinolysis in uPAR null mice rescued nerve repair after sciatic nerve crush. Finally, we measured the fibrinolytic activity in sural nerve biopsies from patients with peripheral neuropathies. We showed that neuropathies with defective regeneration had reduced fibrinolytic activity. On the contrary, neuropathies with signs of active regeneration displayed higher fibrinolytic activity. Overall, our results suggest that enforced fibrinolysis may facilitate regeneration and outcome of peripheral neuropathies.
authors.affiliation: Institute of Experimental Neurology (INSPE), San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Rivellini
authors.forename: Giorgia
authors.initials: G
authors.lastname: Dina
authors.forename: Emanuela
authors.initials: E
authors.lastname: Porrello
authors.forename: Federica
authors.initials: F
authors.lastname: Cerri
authors.forename: Marina
authors.initials: M
authors.lastname: Scarlato
authors.forename: Teuta
authors.initials: T
authors.lastname: Domi
authors.forename: Daniela
authors.initials: D
authors.lastname: Ungaro
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Del Carro
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bolino
authors.forename: Angelo
authors.initials: A
authors.lastname: Quattrini
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Stefano C
authors.initials: SC
authors.lastname: Previtali
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005337:Fibrin / Q000378:metabolism; D005342:Fibrinolysis / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009409:Nerve Crush; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology*; D010523:Peripheral Nervous System Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology*; D055293:Receptors, Urokinase Plasminogen Activator / Q000172:deficiency / Q000378:metabolism*; D011994:Recombinant Proteins / Q000494:pharmacology / Q000627:therapeutic use; D012584:Sciatic Nerve / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D055293:Receptors, Urokinase Plasminogen Activator; D011994:Recombinant Proteins; D005337:Fibrin; D014568:Urokinase-Type Plasminogen Activator