title: Decorin blocks scarring and cystic cavitation in acute and induces scar dissolution in chronic spinal cord wounds.
abstract: In the injured central nervous system (CNS), transforming growth factor (TGF)-β1/2-induced scarring and wound cavitation impede axon regeneration implying that a combination of both scar suppression and axogenic treatments is required to achieve functional recovery. After treating acute and chronic dorsal funicular spinal cord lesions (DFL) in adult rats with the pan-TGF-β1/2 antagonist Decorin, we report that in: (1), acute DFL, the development of all injury parameters was significantly retarded e.g., wound cavity area by 68%, encapsulation of the wound by a glia limitans accessoria (GLA) by 65%, GLA basal lamina thickness by 94%, fibronectin, NG2 and Sema-3A deposition by 87%, 48% and 48%, respectively, and both macrophage and reactive microglia accumulations by 60%; and (2), chronic DFL, all the above parameters were attenuated to a lesser extent e.g., wound cavity area by 11%, GLA encapsulation by 25%, GLA basal lamina thickness by 31%, extracellular fibronectin, NG2 and Sema-3A deposition by 58%, 22% and 29%, respectively, and macrophage and reactive microglia accumulations by 44%. Moreover, in acute and chronic DFL, levels of tissue plasminogen activator (tPA) were raised (by 236% and 482%, respectively), as were active-MMP-2 (by 64% and 91%, respectively) and active-MMP-9 (by 122% and 18%, respectively), while plasminogen activator inhibitor-1 (PAI-1) was suppressed (by 56% and 23%, respectively) and active-TIMP-1 and active TIMP-2 were both lower but only significantly suppressed in acute DFL (by 56 and 21%, respectively). These findings demonstrate that both scar tissue mass and cavitation are attenuated in acute and chronic spinal cord wounds by Decorin treatment and suggest that the dominant effect of Decorin during acute scarring is anti-fibrogenic through suppression of inflammatory fibrosis by neutralisation of TGF-β1/2 whereas, in chronic lesions, Decorin-induction of tPA and MMP (concomitant with reduced complimentary levels of TIMP and PAI-1) leads to dissolution of the mature established scar by fibrolysis. Decorin also promoted the regeneration of similar numbers of axons through acute and chronic wounds. Accordingly, intrathecal delivery of Decorin offers a potential translatable treatment for scar tissue attenuation in patients with spinal cord injury.
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK. Electronic address: z.ahmed.1@bham.ac.uk.
authors.forename: Zubair
authors.initials: Z
authors.lastname: Ahmed
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Daljeet
authors.initials: D
authors.lastname: Bansal
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Tizzard
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Sarina
authors.initials: S
authors.lastname: Surey
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Esmaeili
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Ana Maria
authors.initials: AM
authors.lastname: Gonzalez
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Berry
authors.affiliation: Neurotrauma and Neurodegeneration Section, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
authors.forename: Ann
authors.initials: A
authors.lastname: Logan
mesh_terms: D000208:Acute Disease; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000473:pathology / Q000502:physiology; D002417:Cattle; D002908:Chronic Disease; D002921:Cicatrix / Q000188:drug therapy / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D003094:Collagen; D058575:Decorin / Q000008:administration & dosage / Q000494:pharmacology*; D004343:Drug Implants; D006801:Humans; D008297:Male; D009416:Nerve Regeneration / Q000187:drug effects / Q000502:physiology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology; D013116:Spinal Cord / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D013119:Spinal Cord Injuries / Q000150:complications / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D053773:Transforming Growth Factor beta1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: C546878:DCN protein, human; D058575:Decorin; D004343:Drug Implants; D018696:Neuroprotective Agents; D011994:Recombinant Proteins; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D003094:Collagen
keywords: Decorin; ECM; MMP; Scarring; Spinal cord injury; TIMP; tPA