TY - JOUR
T1 - Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice
AU - Gruss, Claus J.
AU - Satyamoorthy, Kapaettu
AU - Berking, Carola
AU - Lininger, John
AU - Nesbit, Mark
AU - Schaider, Helmut
AU - Liu, Zhao June
AU - Oka, Masahiro
AU - Hsu, Mei Yu
AU - Shirakawa, Takashi
AU - Li, Gang
AU - Bogenrieder, Thomas
AU - Carmeliet, Peter
AU - El-Deiry, Wafik S.
AU - Eck, Stephen L.
AU - Rao, Justi S.
AU - Baker, Andrew H.
AU - Bennet, Jean T.
AU - Crombleholme, Timothy M.
AU - Velazquez, Omaida
AU - Karmacharya, Jagajan
AU - Margolis, David J.
AU - Wilson, James M.
AU - Detmar, Michael
AU - Skobe, Mihaela
AU - Robbins, Paul D.
AU - Buck, Clayton
AU - Herlyn, Meenhard
N1 - Funding Information:
We thank Elsa Aglow for histotechnology support. This work was supported by grants from the NIH, CA 25874, CA 10815, CA76674, CA80999, and the Juvenile Diabetes Foundation. C.J. Gruss was supported by the Department of Dermatology at the University of Regensburg, Regensburg, Germany. We thank Regeneron, Inc., Tarrytown, NY for supplying us with adenoviral vector for Ang-10.
PY - 2003/4/1
Y1 - 2003/4/1
N2 - 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-βs 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.
AB - 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-βs 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.
KW - Adenovirus
KW - Growth factor
KW - Human skin graft
KW - Skin remodelling
UR - http://www.scopus.com/inward/record.url?scp=0037377661&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0037377661&partnerID=8YFLogxK
U2 - 10.1046/j.1523-1747.2003.12112.x
DO - 10.1046/j.1523-1747.2003.12112.x
M3 - Article
C2 - 12648235
AN - SCOPUS:0037377661
SN - 0022-202X
VL - 120
SP - 683
EP - 692
JO - Journal of Investigative Dermatology
JF - Journal of Investigative Dermatology
IS - 4
ER -