title: Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice.
abstract: Reorganization of skin during wound healing, inflammatory disorders, or cancer growth is the result of expression changes of multiple genes associated with tissue morphogenesis. We wanted to identify proteins involved in skin remodeling and select those that may be targeted for agonistic or antagonist therapeutic approaches in various disease processes. Full-thickness human skin was grafted to severe combined immunodeficient mice and injected intradermally with 38 different adenoviral vectors inserted with 37 different genes coding for growth factors, cytokines, proteolytic enzymes and their inhibitors, adhesion receptors, oncogenes, and tumor suppressor genes. Responses were characterized for infiltration of inflammatory cells, vascular density, matrix formation, fibroblast-like cell proliferation, and epidermal hyperplasia. Of the 17 growth factor vectors, 16 induced histological changes in human skin. Members of the VEGF and angiopoietin families induced neovascularization. PDGFs and TGF-betas stimulated connective tissue formation, and the chemokines IL-8 and MCP-1 attracted inflammatory neutrophils and monocytes, respectively. The serine protease uPA induced a vascular response similar to that of VEGF. Vectors with adhesion receptors, oncogenes and tumor suppressor genes had, with few exceptions, little effects on skin architecture. The overall results suggest that adenoviral vectors can effectively remodel the architecture of human skin for studies in morphogenesis, inflammatory skin disorders, wound healing, and cancer development.
authors.affiliation: The Wistar Institute, Philadelphia, PA Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute, Leuven, Belgium.
authors.forename: Claus J
authors.initials: CJ
authors.lastname: Gruss
authors.forename: Kapaettu
authors.initials: K
authors.lastname: Satyamoorthy
authors.forename: Carola
authors.initials: C
authors.lastname: Berking
authors.forename: John
authors.initials: J
authors.lastname: Lininger
authors.forename: Mark
authors.initials: M
authors.lastname: Nesbit
authors.forename: Helmut
authors.initials: H
authors.lastname: Schaider
authors.forename: Zhao-June
authors.initials: ZJ
authors.lastname: Liu
authors.forename: Masahiro
authors.initials: M
authors.lastname: Oka
authors.forename: Mei-Yu
authors.initials: MY
authors.lastname: Hsu
authors.forename: Takashi
authors.initials: T
authors.lastname: Shirakawa
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Thomas
authors.initials: T
authors.lastname: Bogenrieder
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
authors.forename: Stephen L
authors.initials: SL
authors.lastname: Eck
authors.forename: Justi S
authors.initials: JS
authors.lastname: Rao
authors.forename: Andrew H
authors.initials: AH
authors.lastname: Baker
authors.forename: Jean T
authors.initials: JT
authors.lastname: Bennet
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Crombleholme
authors.forename: Omaida
authors.initials: O
authors.lastname: Velazquez
authors.forename: Jagajan
authors.initials: J
authors.lastname: Karmacharya
authors.forename: David J
authors.initials: DJ
authors.lastname: Margolis
authors.forename: James M
authors.initials: JM
authors.lastname: Wilson
authors.forename: Michael
authors.initials: M
authors.lastname: Detmar
authors.forename: Mihaela
authors.initials: M
authors.lastname: Skobe
authors.forename: Paul D
authors.initials: PD
authors.lastname: Robbins
authors.forename: Clayton
authors.initials: C
authors.lastname: Buck
authors.forename: Meenhard
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D002678:Chimera; D016207:Cytokines / Q000235:genetics*; D015870:Gene Expression; D005822:Genetic Vectors; D006133:Growth Substances / Q000235:genetics*; D006801:Humans; D007271:Injections, Intradermal; D051379:Mice; D016513:Mice, SCID; D018919:Neovascularization, Physiologic; D010447:Peptide Hydrolases / Q000235:genetics*; D012867:Skin / Q000098:blood supply / Q000166:cytology; D016038:Skin Transplantation; D014183:Transplantation, Heterologous
chemical_list: D016207:Cytokines; D006133:Growth Substances; D010447:Peptide Hydrolases