Abstract
There is a pressing need for improved preclinical model systems in which to study human skin wound healing. Here, we report the development and application of a serum-free full thickness human skin wound healing model. Not only can re-epithelialization (epidermal repair) and angiogenesis be studied in this simple and instructive model, but the model can also be used to identify clinically relevant wound-healing promoting agents, and to dissect underlying candidate mechanisms of action in the target tissue. We present preliminary ex vivo data to suggest that Thyroxine (T4), which reportedly promotes skin wound healing in rodents in vivo, may promote key features of human skin wound healing. Namely, T4 stimulates re-epithelialisation and angiogenesis, and modulates both wound healing-associated epidermal keratin expression and energy metabolism in experimentally wound human skin. Functionally, the wound healing-promoting effects of T4 are at least partially mediated via fibroblast growth factor/fibroblast growth factor receptor-mediated signalling, since they could be significantly antagonized by bFGF-neutralizing antibody. Thus, this pragmatic, easy-to-use full-thickness human skin wound healing model provides a useful preclinical research tool in the search for clinically relevant candidate wound healing-promoting agents. These ex vivo data encourage further pre-clinical testing of topical T4 as a cost-efficient, novel agent in the management of chronic human skin wounds.
Highlights
Retarded healing of human skin wounds, which may result in ulceration, represents an increasing, global healthcare and quality-of-life challenge, especially in the context of an aging population [1,2,3,4,5]
Overall skin morphology was well-preserved until and including day 6 of organ culture, during which time no epidermal detachment from the basal membrane was seen, while the number of proliferating or apoptotic keratinocytes in the epidermis and hair follicle (HF) (Ki-67/terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) immunofluorescence microscopy) during the entire study window of 6 days was within the expected normal range [26, 38]
Proliferation and apoptosis in the epithelial tongue (ET) were not significantly modulated by T4, as measured by quantitative immunohistomorphometry of Ki67+ or terminal deoxynucleotidyl transferase dUTP nick end labelling-positive (TUNEL+) cells in ETs (Fig 2e–2h). This may reflect the well-recognized complexity of T4’s effects on the overall tissue modelling process, which represents a balance of keratinocyte proliferation, apoptosis, differentiation and migration effects [33]
Summary
Retarded healing of human skin wounds, which may result in ulceration, represents an increasing, global healthcare and quality-of-life challenge, especially in the context of an aging population [1,2,3,4,5]. In order to meet this need, it is critical to have simple and pragmatic, predictive model systems in which new candidate promoters of human skin wound healing can be instructively studied at the preclinical level [7, 8]. We and others have advocated the use of experimentally wounded full-thickness human skin ex vivo, ideally under defined, serumfree organ culture conditions, as well as the systematic testing of agents that have already been licensed for clinical use [7]. L-thyroxine (T4) promotes human hair growth [19] and stimulates wound healing in vivo in rats [31] and mice [32]. The potential clinical utility of T4 in a dermatological setting, namely as a candidate wound healing promoter, is yet to be fully explored [30]
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