Thyrotropin-Releasing Hormone (TRH) Promotes Wound Re-Epithelialisation in Frog and Human Skin

Abstract

There remains a critical need for new therapeutics that promote wound healing in patients suffering from chronic skin wounds. This is, in part, due to a shortage of simple, physiologically and clinically relevant test systems for investigating candidate agents. The skin of amphibians possesses a remarkable regenerative capacity, which remains insufficiently explored for clinical purposes. Combining comparative biology with a translational medicine approach, we report the development and application of a simple ex vivo frog (Xenopus tropicalis) skin organ culture system that permits exploration of the effects of amphibian skin-derived agents on re-epithelialisation in both frog and human skin. Using this amphibian model, we identify thyrotropin-releasing hormone (TRH) as a novel stimulant of epidermal regeneration. Moving to a complementary human ex vivo wounded skin assay, we demonstrate that the effects of TRH are conserved across the amphibian-mammalian divide: TRH stimulates wound closure and formation of neo-epidermis in organ-cultured human skin, accompanied by increased keratinocyte proliferation and wound healing-associated differentiation (cytokeratin 6 expression). Thus, TRH represents a novel, clinically relevant neuroendocrine wound repair promoter that deserves further exploration. These complementary frog and human skin ex vivo assays encourage a comparative biology approach in future wound healing research so as to facilitate the rapid identification and preclinical testing of novel, evolutionarily conserved, and clinically relevant wound healing promoters.

Thyroid Hormones Enhance Mitochondrial Function in Human Epidermis

“…However, it is unlikely that the putative anti-aging effects of THs can be explained by wound healing inhibition. THs actually promote wound healing, a highly energy-consumptive process, in murine skin in vivo (Kassem et al, 2012;Safer, 2012;Safer et al, 2005) and promotes reepithelialization in experimentally wounded organ-cultured human skin (Meier et al, 2013) ex vivo (Paus lab, unpublished observation), while mice devoid of the TR-alpha and -beta show retarded wound-healing (Contreras-Jurado et al, 2014;Safer et al, 2005). Moreover, all in situ analyses reported here where purposely performed distant from the periphery of the organ-cultured skin fragments, thus lowering the risk to confound aging-related phenomena with superimposed wound M A N U S C R I P T A C C E P T E D ACCEPTED MANUSCRIPT 9 healing processes (for detailed discussion of wound healing-related skin responses as a potential confounding element in the current study, see Supplementary Text S1).…”

Short-term cadmium exposure induces stress responses in frog (Pelophylax bergeri) skin organ culture

“…Previous researches conducted in different organisms such as humans, pig and frog demonstrated that skin organ culture was successfully maintained for several days, without any structural changes. These findings show that skin organ culture can be used for testing chemical compounds and for investigating different physiological and pathological conditions (Varani et al, 2007;Dame et al, 2008;Jacques et al, 2010;Lebonvallet et al, 2010;Kleszczyński and Fischer, 2012;Meier et al, 2013).…”

“…In the present study the potential Cd-induced stress responses were examined in adult amphibian P. bergeri skin using an ex-vivo full-thickness skin organ culture as the experimental model to study cellular and molecular stress responses. Amphibian organ culture has been used extensively as a valid biological tool for many research issues (Monnickendam and Balls, 1973;Van Rooij et al, 2010;Groot et al, 2012;Meier et al, 2013). Currently, in vitro cultures are being used in both cytotoxic risk assessment and for field evaluation of toxic environmental contaminants.…”

Role of regeneration in tissue repairing and therapies

“…Scleraxis is a key transcription factor which is recognized essential for tenogenic and ligamentogenic differentiation. Similarly, collagen fibers are ubiquitous macromolecular assemblies in nature, which form structures that support tensile mechanical loads within the human body [110]. Thus, aligned type I collagen fibers are considered more workable primary structural motif for tendon and ligament regeneration.…”

“…Therefore, construction of complex and challenging biomaterials, may improve the mechanical function of tendons and ligaments. Further, potential for tailoring and manipulating the interactions between collagen fibers and biological systems, as hybrid biomaterialbiological assemblages, will help to develop novel tissue engineering strategies for tendon and ligament regeneration [110]. However, semitendinosus tendon can regenerate after being harvested in its whole length and thickness for anterior cruciate ligament (ACL) reconstruction, but it is not applicable to make a neo-tendon.…”