title: Gene delivery of a mutant TGFβ3 reduces markers of scar tissue formation after cutaneous wounding.
abstract: The transforming growth factor-β (TGFβ) family plays a critical regulatory role in repair and coordination of remodeling after cutaneous wounding. TGFβ1-mediated chemotaxis promotes the recruitment of fibroblasts to the wound site and their resultant myofibroblastic transdifferentiation that is responsible for elastic fiber deposition and wound closure. TGFβ3 has been implicated in an antagonistic role regulating overt wound closure and promoting ordered dermal remodeling. We generated a mutant form of TGFβ3 (mutTGFβ3) by ablating its binding site for the latency-associated TGFβ binding protein (LTBP-1) in order to improve bioavailability and activity. The mutated cytokine is secreted as the stable latency-associated peptide (LAP)-associated form and is activated by normal intracellular and extracellular mechanisms including integrin-mediated activation but is not sequestered. We show localized intradermal transduction using a lentiviral vector expressing the mutTGFβ3 in a mouse skin wounding model reduced re-epithelialization density and fibroblast/myofibroblast transdifferentiation within the wound area, both indicative of reduced scar tissue formation.
authors.affiliation: Institute for Women's Health, University College London, London, UK. s.waddington@imperial.ac.uk
authors.forename: Simon N
authors.initials: SN
authors.lastname: Waddington
authors.forename: Rachel
authors.initials: R
authors.lastname: Crossley
authors.forename: Vicky
authors.initials: V
authors.lastname: Sheard
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Howe
authors.forename: Suzanne M K
authors.initials: SM
authors.lastname: Buckley
authors.forename: Lynda
authors.initials: L
authors.lastname: Coughlan
authors.forename: David E
authors.initials: DE
authors.lastname: Gilham
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hawkins
authors.forename: Tristan R
authors.initials: TR
authors.lastname: McKay
mesh_terms: D000818:Animals; D002921:Cicatrix / Q000473:pathology; D015316:Genetic Therapy; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D009154:Mutation; D012867:Skin / Q000473:pathology; D053782:Transforming Growth Factor beta3 / Q000235:genetics*; D014945:Wound Healing / Q000235:genetics / Q000502:physiology*
chemical_list: D053782:Transforming Growth Factor beta3