Non-viral liposomal keratinocyte growth factor (KGF) cDNA gene transfer improves dermal and epidermal regeneration through stimulation of epithelial and mesenchymal factors

Keratinocyte growth factor (KGF) stimulates epithelial cell differentiation and proliferation, which are of major importance for wound healing. Local protein administration, however, has been shown to be ineffective due to enzymes and proteases in the wound fluid. We hypothesized that delivering KGF...

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Bibliographic Details
Published in:	Gene therapy Vol. 9; no. 16; pp. 1065 - 1074
Main Authors:	JESCHKE, M. G, RICHTER, G, HÖFSTÖDTER, F, HERNDON, D. N, PEREZ-POLO, J-R, JAUCH, K-W
Format:	Journal Article
Language:	English
Published:	Basingstoke Nature Publishing Group 01-08-2002
Subjects:	Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Animals Apoptosis Applied cell therapy and gene therapy Biological and medical sciences Biotechnology Burns - metabolism Burns - pathology Burns - therapy Cell differentiation Cell Division Cell proliferation Collagen Collagen - metabolism DNA, Complementary - administration & dosage Epidermis - physiology Epithelial cells Fibroblast Growth Factor 7 Fibroblast Growth Factors - genetics Fibroblast Growth Factors - metabolism Fundamental and applied biological sciences. Psychology Gene therapy Gene transfer Gene Transfer Techniques Genetic Therapy - methods Growth factors Health. Pharmaceutical industry Industrial applications and implications. Economical aspects Insulin-like growth factor I Insulin-Like Growth Factor I - metabolism Keratinocyte growth factor LacZ gene Liposomes Male Medical sciences Mesenchyme Rats Rats, Sprague-Dawley Regeneration Skin Skin - pathology Skin Physiological Phenomena Transfection Transfusions. Complications. Transfusion reactions. Cell and gene therapy Vascular endothelial growth factor Vascularization Wound Healing β-Galactosidase Animal model Rat Rodentia Liposome Epidermis Artificial membrane Keratinocyte growth factor Insulin like growth factor 1 Wound Genetic transfer Regeneration Vertebrata Mammalia Vascular endothelium growth factor Reporter gene Complementary DNA Derm Gene therapy
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Summary:	Keratinocyte growth factor (KGF) stimulates epithelial cell differentiation and proliferation, which are of major importance for wound healing. Local protein administration, however, has been shown to be ineffective due to enzymes and proteases in the wound fluid. We hypothesized that delivering KGF as a non-viral liposomal cDNA gene complex is a new approach that would effectively enhance dermal and epidermal regeneration. Twenty-two rats were given an acute wound and divided into two groups to receive weekly subcutaneous injections of liposomes plus the LacZ gene (0.2 microg, vehicle), or liposomes plus the KGF cDNA (2.2 microg) and LacZ cDNA (0.2 microg). Transfection was confirmed by histochemical assays for beta-galactosidase. Planimetry, histological and immunohistochemical techniques were used to determine protein expression, dermal and epidermal regeneration. Transfection and subsequent KGF expression was found in diving cells in the granulation tissue. Epidermal regeneration was improved by 170% in rats receiving the KGF cDNA constructs by exhibiting the most rapid area and linear wound re-epithelialization, P < 0.0001. KGF improved epidermal cell net balance by increasing skin cell proliferation and decreasing skin cell apoptosis, P < 0.0001. Dermal regeneration was further improved in KGF cDNA treated animals by an increased collagen deposition and morphology, P < 0.0001. KGF cDNA increased neo-vascularization and concomitant VEGF concentrations when compared with vehicle, P < 0.01. KGF cDNA did not only stimulate epithelial cells, but also mesenchymal cells through increases in IGF-I concentration, P < 0.005. Liposomes containing the KGF cDNA gene constructs were effective in improving epidermal and dermal regeneration. KGF gene transfer to acute wounds may represent a new therapeutic strategy to enhance wound healing.
Bibliography:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2
ISSN:	0969-7128 1476-5462
DOI:	10.1038/sj.gt.3301732