1. ¹The Wistar Institute, Philadelphia, PA
2. ²Center for Transgene Technology and Gene Therapy, Flanders Interuniversity Institute, Leuven, Belgium
3. ³Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania, Philadelphia, PA
4. ⁴Department of Medicine, University of Pennsylvania, School of Medicine, Philadelphia, PA
5. ⁵Department of Neurosurgery, University of Texas, M.D. Anderson Cancer Center, Houston, TX
6. ⁶Department of Medicine and Therapeutics, University of Glasgow, UK
7. ⁷Department of Ophthalmology, University of Pennsylvania, Philadelphia, PA
8. ⁸Children's Institute for Surgical Science at the Children's Hospital of Philadelphia, University of Pennsylvania, Philadelphia, PA
9. ⁹Department of Surgery, University of Pennsylvania, Philadelphia, PA
10. ¹⁰Department of Biostatistics and Epidemiology, University of Pennsylvania, Philadelphia, PA
11. ¹¹Institute for Human Gene Therapy and Department of Molecular and Cellular Engineering, University of Pennsylvania, Philadelphia, PA
12. ¹²Cutaneous Biology Research Center, Massachusetts General Hospital East and Harvard Medical School, Charlestown, MA
13. ¹³Department of Orthopedic Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

Correspondence: Dr Meenhard Herlyn, The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. E-mail: Herlynm@wistar.upenn.edu

Received 5 August 2001; Revised 6 February 2002; Accepted 8 August 2002.

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-s 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.