Exogenous liposomal IGF-I cDNA gene transfer leads to endogenous cellular and physiological responses in an acute wound.

The purpose of the present study was to examine whether exogenous liposomal cDNA gene transfer is recognized by the cell and causes endogenous cellular and physiological responses. When administered as a protein, IGF-I is known to cause adverse side effects due to lack of cellular responses. Therefore, we used IGF-I cDNA as a vector to study cellular and physiological effects after liposomal administration to wounded skin. Sprague-Dawley rats were given a scald burn to inflict an acute wound and were divided into two groups to receive weekly subcutaneous injections of liposomes plus the Lac-Z gene (0.2 microg vehicle) or liposomes plus the IGF-I cDNA (2.2 microg) and Lac Z gene (0.22 microg). Transfection was confirmed by histochemical assays for beta-galactosidase. Planimetry, immunological assays, and histological and immunohistochemical techniques were used to determine molecular mechanisms after gene transfer, protein expression, and dermal and epidermal regeneration. IGF-I cDNA transfer increased IGF-I protein expression and caused concomitant cellular responses by increasing IGF binding protein (IGFBP)-3 and decreasing IGFBP-1. IGF-I cDNA gene transfer increased keratinocyte growth factor expression and exerted promitogenic antiapoptotic effects on basal keratinocytes, thus improving epidermal regeneration. IGF-I cDNA improved dermal regeneration by an increased collagen deposition and morphology. IGF-I cDNA increased VEGF concentrations and thus neovascularization. Exogenous-administered IGF-I cDNA is recognized by the cell and leads to similar intracellular responses as the endogenous gene. Liposomal IGF-I gene transfer further leads to improved dermal and epidermal regeneration by interacting with other growth factors.

[1]  K. Jauch,et al.  Therapeutic success and efficacy of nonviral liposomal cDNA gene transfer to the skin in vivo is dose dependent , 2001, Gene Therapy.

[2]  Xiaodong Feng,et al.  Angiogenesis in wound healing. , 2000, The journal of investigative dermatology. Symposium proceedings.

[3]  J. Vogel,et al.  Nonviral skin gene therapy. , 2000, Human gene therapy.

[4]  R. Barrow,et al.  Biodistribution and Feasibility of Non-Viral IGF-I Gene Transfers in Thermally Injured Skin , 2000, Laboratory Investigation.

[5]  N. Ferrara,et al.  Vascular endothelial growth factor and the regulation of angiogenesis. , 2000, Recent progress in hormone research.

[6]  H. Kleinman,et al.  Impaired wound repair and delayed angiogenesis in aged mice. , 1999, Laboratory investigation; a journal of technical methods and pathology.

[7]  A. Singer,et al.  Cutaneous wound healing. , 1999, The New England journal of medicine.

[8]  R. Barrow,et al.  IGF-I gene transfer in thermally injured rats , 1999, Gene Therapy.

[9]  D. Lacey,et al.  Keratinocyte growth factor protects murine hepatocytes from tumor necrosis factor–induced apoptosis in vivo and in vitro , 1998, Hepatology.

[10]  S. Werner,et al.  Keratinocyte growth factor: a unique player in epithelial repair processes. , 1998, Cytokine & growth factor reviews.

[11]  J. Rubin,et al.  Differential expression of the keratinocyte growth factor (KGF) and KGF receptor genes in human vascular smooth muscle cells and arteries , 1997, Journal of cellular physiology.

[12]  P. Felgner.  Nonviral strategies for gene therapy. , 1997, Scientific American.

[13]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[14]  Liying Sun,et al.  Transfection with aFGF cDNA improves wound healing. , 1997, The Journal of investigative dermatology.

[15]  R. Akhurst,et al.  Liposome-medicated gene transfer and expression via the skin. , 1995, Human molecular genetics.

[16]  J. Rubin,et al.  Keratinocyte growth factor , 1995, Cell biology international.

[17]  P. Hofschneider,et al.  The function of KGF in morphogenesis of epithelium and reepithelialization of wounds. , 1994, Science.

[18]  H. Steenfos,et al.  Growth factors and wound healing. , 1994, Scandinavian journal of plastic and reconstructive surgery and hand surgery.

[19]  N. Fusenig,et al.  Mutual induction of growth factor gene expression by epidermal-dermal cell interaction , 1993, The Journal of cell biology.

[20]  R. Humbel,et al.  Insulin-like growth factors I and II. , 1990, European journal of biochemistry.

[21]  R. Baxter,et al.  Circulating levels and molecular distribution of the acid-labile (alpha) subunit of the high molecular weight insulin-like growth factor-binding protein complex. , 1990, The Journal of clinical endocrinology and metabolism.

[22]  J. Rubin,et al.  Human KGF is FGF-related with properties of a paracrine effector of epithelial cell growth. , 1989, Science.

[23]  A. Mason,et al.  Development and analysis of a small animal model simulating the human postburn hypermetabolic response. , 1978, The Journal of surgical research.