postdoc Koltzov Institute of Developmental Biology of Russian Academy of Sciences, Russia
Abstract: The transcription cofactor YES-associated protein (YAP) regulates migration, proliferation, and the reaction to injury in a variety of tissues and organs. The Hippo pathway inhibits YAP activity and preserves it in the cytoplasm. The importance of the Hippo/YAP pathway for maintaining epidermal homeostasis was demonstrated by altering YAP activity in mouse skin through genetic modifications and by analyzing human skin samples from donors with different diseases. Active nuclear YAP was found in individual cells in the basal layer of the epidermis in healthy human skin. We verified that an abnormal active YAP distribution was present in pathology: most epidermal nuclei were YAP-positive in fibrotic circumstances, but YAP expression declined in chronic wounds. We recently demonstrated, using a human skin xenograft model, that YAP activity decreased during human skin regeneration, which is associated with a decline in keratinocyte proliferation and epidermal rete ridge repair. We applied primary epidermal keratinocytes, HaCaT and A431 cell lines, to describe the cell phenotype under YAP activation or suppression by western blot, immunohistochemistry, and qPCR. We activated YAP signaling using Hippo inhibitor Truli. It dramatically decreased the expression of KLF4 and keratin 1/10, which are linked to epidermal differentiation. Similarly, the expression of basal markers keratin 15 and collagen 17a was downregulated. This was accompanied by an increase in the rate of proliferation. We did not identify any significant alterations in basal keratin 5/14 or wound-response keratin 6 expression. We used shRNA to inhibit YAP expression. It increased expression of differentiation markers and suppressed proliferation. Both YAP activation and inhibition did not influence keratinocyte migration in the wound-scratch test. Summing up, active YAP correlates with low-differentiated and highly proliferative conditions of epidermal keratinocytes that correspond to transit-amplifying cell state rather than basal stem cell state or wound-response phenotype.
Funding Source: This research was funded by the Russian Science Foundation (project no. 21-74-30015-π, prolongation of rscf.ru/en/project/21-74-30015/ (accessed on 4 March 2025)).
