The state of the skin changes drastically depending on the ambient temperature. Skin epidermal keratinocytes express thermosensitive transient receptor potential vanilloid (TRPV) cation channels, TRPV3 and TRPV4. These multimodal receptors are activated by various kinds of chemical and physical stimuli, including warm temperatures (>30°C). It has been suggested that TRPV4 is involved in cell-cell junction maturation; however, the effect of temperature fluctuations on TRPV4-dependent barrier homeostasis is unclear. In the present study, we demonstrated that activation of TRPV4 was crucial for barrier formation and recovery, both of which were critical for the prevention of excess dehydration of human skin keratinocytes. TRPV4 activation by physiological skin temperature (33°C), GSK1016790A or 4α-PDD allowed influx of Ca(2+) from extracellular spaces which promoted cell-cell junction development. These changes resulted in augmentation of intercellular barrier integrity in vitro and ex vivo. TRPV4 disruption reduced the increase in trans-epidermal resistance and increased intercellular permeation after a Ca(2+) switch. Furthermore, barrier recovery after the disruption of the stratum corneum was accelerated by the activation of TRPV4 either by warm temperature or a chemical activator. Our results suggest that physiological skin temperatures play important roles in cell-cell junction and skin barrier homeostasis through TRPV4 activation.

As a major intracellular degradation system, autophagy contributes to the maintenance of skin keratinocyte homeostasis. However, the precise role of autophagy in skin differentiation has not been fully investigated. To clarify whether autophagy plays a role in skin differentiation and maturation, autophagy-related gene 7 (Atg7)-deficient mice were generated. Atg7-deficient mice cannot survive for more than 24 h after birth. Therefore, the skins of Atg7-deficient mice and wild-type mice (as a control) were grafted onto severe combined immunodeficient mice. The resulting morphological and pathological changes were monitored for 28 days. Histopathological examination revealed acanthosis, hyperkeratosis, and abnormal hair growth in the skin grafts from the Atg7-deficient mice. Immune-density analysis of the skin grafts revealed reduced immunostaining of keratinization-related proteins, including loricrin, filaggrin, and involucrin, in the skin grafts from the Atg7-deficient mice. Furthermore, quantitative RT-PCR and Western blot analyses revealed the reduced expression of these three keratinization-related proteins in the skin grafts from the Atg7-deficient mice. Morphometric analysis using electron microscopy further revealed a reduction in the number and diameter of the keratohyalin and trichohyalin granules in these skin grafts. The differences were maintained for at least 1 month after transplantation. These results show that autophagy has a significant role in epidermal keratinization and hair growth until a certain stage of maturation.

No abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a disease characterized by recurrent blistering and chronic ulceration of the skin. In these patients, recurrent blisters frequently result in intractable skin ulcers due to impaired wound healing caused by mutations in the type VII collagen gene and malnutrition as well as by increased collagenase activity. To evaluate the efficacy of amnia for intractable ulcers in RDEB, we treated RDEB patients with amnia. The amniotic membrane was simply placed on the cleansed wound surface. The procedure was repeated once a week for up to 10 weeks. As a result, wound conditions improved remarkably after treatment with amnia for 2-10 weeks in all the patients, resulting in total re-epithelization of the ulcers. Amnia could be an effective therapy for intractable skin ulcers in RDEB patients, and should be considered as a re-emerging therapeutic option for the disease.

No abstract