Thyroxine (T4) may promote re-epithelialisation and angiogenesis in wounded human skin ex vivo

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.

Vascular Endothelial Growth Factor Blockade Induces Dermal Endothelial Cell Apoptosis in a Clinically Relevant Skin Organ Culture Model

“…To achieve this, readily available and clinically relevant preclinical research assays are required, with full-thickness serum-free human skin organ culture providing one pragmatic option. These simple and experimentally tractable ex vivo assays are more likely to reflect relevant cellcell, cell-matrix, and tissue interactions in human skin in situ than 3D or 2D angiogenesis assay systems [8][9][10]. Most importantly, utilizing organ-cultured skin biopsies from dermatological conditions such as psoriasis offers the opportunity to interrogate the angiogenic effect of xenobiotic molecules in a clinically relevant preclinical model.…”

Topical L‐thyroxine: The Cinderella among hormones waiting to dance on the floor of dermatological therapy?

“…There is multiple level evidence that TH should promote wound healing (WH) in human skin, ranging from clinical data from patients with hypothyroidism to various experimental in vivo, ex vivo and in vitro models 7,93,[149][150][151] (see also below, "Skin ulcer management"). It is assumed that hypothyroidism is associated with delayed WH, 152 and T4 reportedly is necessary for the healing of radiotherapy-induced neck fistula in hypothyroid patients.…”

“…156 Nevertheless, a host of in vivo data from hypothyroid rats and mice as well as ex vivo evidence from experimentally wounded human skin demonstrate a key role for THs in WH. 93,151,[157][158][159] Mice treated with systemic (intra-peritoneal) T3 achieved a WH rate that was twice the rate of TH-deficient mice, 93 and oral T3 also led to improved quality of wounds and increased the healing rate in rats. 157,159 The same WH promoting effect was achieved in mice treated with topical T3 and in rats treated with the combination of Aloe vera, TH and silver sulfadiazine.…”

“…The relentlessly expanding "ulcer epidemic" is one of the most significant healthcare challenges faced by medical systems around the globe. 167,168 Given hypothyroidism-associated WH abnormalities, 7,160 direct evidence that topical T3 and T4 promotes acute WH in mice in vivo 93 and that T4 promotes epidermal repair and possibly even angiogenesis in wounded human skin ex vivo, 151 171 should also facilitate WH under the severely hypoxic conditions that characterize most skin ulcers. [172][173][174] We therefore advocate to rigorously explore whether topical T4…”

Natural Products and/or Isolated Compounds on Wound Healing

“…With an increase in the prevalence of wounds and the high cost of orthodox medicines, most patients, especially those in developing countries, resort to herbal preparations or remedies which are believed to be readily available and cheap for the treatment thereof. The urgent need for the identification of effective, safe, and cost efficient wound healing promoters which can be introduced into clinical practice is unequivocal [2, 3]. This has driven an increase in the search for potent, cost effective wound healing agents from natural products including medicinal plants.…”