Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice

Claus J. Gruss, Kapaettu Satyamoorthy, Carola Berking, John Lininger, Mark Nesbit, Helmut Schaider, Zhao June Liu, Masahiro Oka, Mei Yu Hsu, Takashi Shirakawa, Gang Li, Thomas Bogenrieder, Peter Carmeliet, Wafik S. El-Deiry, Stephen L. Eck, Justi S. Rao, Andrew H. Baker, Jean T. Bennet, Timothy M. Crombleholme, Omaida VelazquezJagajan Karmacharya, David J. Margolis, James M. Wilson, Michael Detmar, Mihaela Skobe, Paul D. Robbins, Clayton Buck, Meenhard Herlyn

Research output: Contribution to journalArticle

38 Scopus citations

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-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.

Original languageEnglish (US)
Pages (from-to)683-692
Number of pages10
JournalJournal of Investigative Dermatology
Volume120
Issue number4
DOIs
StatePublished - Apr 1 2003
Externally publishedYes

Keywords

  • Adenovirus
  • Growth factor
  • Human skin graft
  • Skin remodelling

ASJC Scopus subject areas

  • Dermatology

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  • Cite this

    Gruss, C. J., Satyamoorthy, K., Berking, C., Lininger, J., Nesbit, M., Schaider, H., Liu, Z. J., Oka, M., Hsu, M. Y., Shirakawa, T., Li, G., Bogenrieder, T., Carmeliet, P., El-Deiry, W. S., Eck, S. L., Rao, J. S., Baker, A. H., Bennet, J. T., Crombleholme, T. M., ... Herlyn, M. (2003). Stroma formation and angiogenesis by overexpression of growth factors, cytokines, and proteolytic enzymes in human skin grafted to SCID mice. Journal of Investigative Dermatology, 120(4), 683-692. https://doi.org/10.1046/j.1523-1747.2003.12112.x