title: Reduction of hypertrophic scar via retroviral delivery of a dominant negative TGF-beta receptor II.
abstract: Effective blockade of the pluripotent cytokine transforming growth factor (TGF)-beta as a means of cutaneous scar reduction is a strategy with great potential. This desired effect may be achieved through the overexpression of mutant TGF-beta receptors within the wound milieu. Our goal was to examine the effects of dominant negative mutant TGF-beta receptor II (TGFbetaRIIdn) protein expression in a well-established rabbit ear model of hypertrophic scarring. Serial injections of a retroviral construct encoding a truncated TGFbetaRII and the marker green fusion protein (pMSCV-rIIdn-GFP) were performed in 7mm punch wounds at day 10 and day 12 (two-day injection group) or days 8, 10, 12 (three-day injection group) post-wounding. Delivery of an empty vector (pMSCV-GFP) at the same time points served as a negative control. Histomorphometric analysis of wounds harvested at day 28 revealed a modest, though statistically significant reduction (20%, p=0.027) in the scar elevation index (SEI) in two-day treated and a more modest reduction in SEI (12%) in the three-day treated arm compared to null-treated controls. Confocal microscopy confirmed stable, yet variable transfection of the construct in both peri-wound tissue as well as rabbit dermal fibroblasts transfected in vitro. Optimisation of this novel application in retroviral gene therapy could lead to effective anti-scarring strategies.
authors.affiliation: Division of Plastic Surgery, Feinberg School of Medicine, Northwestern University, 675 North Saint Clair, Suite 19-250, Chicago, IL 60611, USA.
authors.forename: Russell R
authors.initials: RR
authors.lastname: Reid
authors.forename: Nakshatra
authors.initials: N
authors.lastname: Roy
authors.forename: Jon E
authors.initials: JE
authors.lastname: Mogford
authors.forename: Hannah
authors.initials: H
authors.lastname: Zimmerman
authors.forename: Chung
authors.initials: C
authors.lastname: Lee
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Mustoe
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000032:analysis; D002460:Cell Line; D017439:Cicatrix, Hypertrophic / Q000473:pathology / Q000628:therapy*; D004195:Disease Models, Animal; D004423:Ear; D015870:Gene Expression / Q000235:genetics; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics / Q000276:immunology; D049452:Green Fluorescent Proteins / Q000032:analysis; D007271:Injections, Intradermal; D018613:Microscopy, Confocal / Q000379:methods; D009154:Mutation / Q000235:genetics; D017346:Protein Serine-Threonine Kinases; D011817:Rabbits; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000008:administration & dosage* / Q000276:immunology; D012190:Retroviridae / Q000235:genetics; D014162:Transfection / Q000379:methods; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000276:immunology / Q000378:metabolism*
chemical_list: D015415:Biomarkers; D018125:Receptors, Transforming Growth Factor beta; D016212:Transforming Growth Factor beta; D049452:Green Fluorescent Proteins; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II