An in vivo model of wound healing in genetically modified skin-humanized mice.
Cutaneous wound-healing disorders are a major health problem that requires the development of innovative treatments. Whithin this context, the search for reliable human wound-healing models that allow us to address both mechanistic and therapeutic matters is warranted. In this study, we have developed a novel invivo wound-healing model in a genetically modified human context. Our model is based on the regeneration of human skin on the back of nude mice by transplantation of a cultured bioengineered skin equivalent previously designed in our laboratory. In this setting, human keratinocytes in the epidermal compartment were genetically modified with a retroviral vector encoding the enhanced green fluorescent protein (EGFP). After stable engraftment of the EGFP skin was achieved (9-12 wk after grafting), a small circular full thickness wound was performed on this mature human skin. A wide variety of parameters involved in wound healing were monitored, including tissue architecture, cell proliferation, epidermal differentiation, dermal remodelling, and basement membrane regeneration. Wounded gene-targeted skin-humanized mice re-capitulated native skin wound-healing features. In addition, when keratinocyte growth factor (KGF), a growth factor that has been shown to improve wound healing, was added to wounds during 3 d, the re-epithelialization was significantly accelerated. The present wound-healing model system provides a suitable in vivo tool to test gene transfer strategies for human skin repair. It also serves as a complementary platform for studies in genetically modified mice and as a model to evaluate pharmaceutical therapeutic approaches for impaired wound healing.
Escámez
María José
MJ
Epithelial Damage, Repair and Tissue Engineering, Ciemat-Fundación Marcelino Botín, Madrid, Spain.
García
Marta
M
Larcher
Fernando
F
Meana
Alvaro
A
Muñoz
Evangelina
E
Jorcano
Jose Luis
JL
Del Río
Marcela
M
D000818:Animals; D002454:Cell Differentiation; D002455:Cell Division; D002478:Cells, Cultured; D020405:Dermis / Q000166:cytology / Q000293:injuries* / Q000502:physiology; D004195:Disease Models, Animal; D000078404:Epidermal Cells; D004817:Epidermis / Q000293:injuries* / Q000502:physiology; D005109:Extracellular Matrix / Q000502:physiology; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors / Q000494:pharmacology; D015316:Genetic Therapy; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000502:physiology; D051379:Mice; D008819:Mice, Nude; D012038:Regeneration / Q000502:physiology; D016038:Skin Transplantation; D023822:Tissue Engineering; D014945:Wound Healing / Q000187:drug effects / Q000502:physiology*; D014947:Wounds and Injuries / Q000188:drug therapy / Q000503:physiopathology*
C496453:FGF7 protein, human; C496454:Fgf7 protein, mouse; D051523:Fibroblast Growth Factor 7; D005346:Fibroblast Growth Factors