The Role of YAP/TAZ Signaling in Human Skin Regeneration

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) play important roles in tissue regeneration, mechanosensory, tissue homeostasis, angiogenesis and prevention of premature aging. In normal skin, YAP/TAZ maintain a balance between proliferation and differentiation and are involved in the formation of the pathologically activated phenotype of epidermal keratinocytes. The property of YAP/TAZ signalling to enhance cell proliferation and activation may lead to the development and progression of psoriasis and cancer when deregulated. Drugs based on modulation of the YAP/TAZ signalling are being developed for the therapy of chronic wounds, tumor and psoriatic skin lesions. There is a lack of understanding of the involvement of YAP/TAZ in the normal differentiation or pathological activation of human skin epidermal keratinocytes, which increases the risk of unforeseen effects of therapy and may hinder the development of more effective approaches. The aim of this work was to study the role of the YAP/TAZ signalling during normal and pathological differentiation of human skin epidermal keratinocytes. Our finding suggest that NHKs are a more representative model of human epidermis keratinocytes than HaCaT but they are less susceptible to genetic methods of YAP/TAZ signaling modulation, while small-molecule YAP/TAZ signaling inhibitors proved to be less specific and cause off-target effects. YAP/TAZ signaling inhibition in HaCaT promoted an early differentiation phenotype, downregulating basal keratinocyte markers, upregulating differentiation markers, and delaying late differentiation. However, differentiation of NHKs after YAP/TAZ inhibition was less pronounced compared to HaCaT cells due to the low specificity of inhibitors. Contrariwise, YAP/TAZ signaling activation in NHKs has a tendency to prevent differentiation and promote a basal layer-like gene expression pattern. We also concluded that YAP/TAZ signaling inhibition suppresses an activated epidermal cell phenotype in HaCaT and NHK cells. This study expanded the understanding of YAP/TAZ signalling in the context of homeostasis, proliferation and differentiation, which is of great fundamental importance. Understanding the general mechanisms of YAP/TAZ signalling will lay the foundation for future studies of human skin regeneration, psoriasis and wound healing therapies. The findings will make important practical contributions to the development of therapeutic options for skin cancer and psoriasis and the search for potential therapy targets among YAP/TAZ-regulated genes, as well as help predict the possible consequences and side effects of YAP/TAZ targeting therapy interventions.