Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice.
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.
Gruss
Claus J
CJ
The Wistar Institute, Philadelphia, PA Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute, Leuven, Belgium.
Satyamoorthy
Kapaettu
K
Berking
Carola
C
Lininger
John
J
Nesbit
Mark
M
Schaider
Helmut
H
Liu
Zhao-June
ZJ
Oka
Masahiro
M
Hsu
Mei-Yu
MY
Shirakawa
Takashi
T
Li
Gang
G
Bogenrieder
Thomas
T
Carmeliet
Peter
P
El-Deiry
Wafik S
WS
Eck
Stephen L
SL
Rao
Justi S
JS
Baker
Andrew H
AH
Bennet
Jean T
JT
Crombleholme
Timothy M
TM
Velazquez
Omaida
O
Karmacharya
Jagajan
J
Margolis
David J
DJ
Wilson
James M
JM
Detmar
Michael
M
Skobe
Mihaela
M
Robbins
Paul D
PD
Buck
Clayton
C
Herlyn
Meenhard
M
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
D016207:Cytokines; D006133:Growth Substances; D010447:Peptide Hydrolases