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This study identifies podoplanin, a small transmembrane protein, as a critical regulator of skin development and inflammatory responses. Using mouse models with podoplanin deletion, researchers found that loss of this protein disrupts the organization of the basal epidermal layer, alters cell division patterns, and uncouples differentiation marker expression from functional barrier maturation during skin development. In adult skin, podoplanin deletion in keratinocytes impairs responses to inflammatory stress, affecting both epidermal stem cell behavior and dermal tissue remodeling, demonstrating that keratinocyte podoplanin coordinates responses across tissue compartments.
Why it matters
Understanding how podoplanin regulates skin barrier formation and inflammatory responses could inform therapeutic approaches for skin disorders involving impaired barrier function or chronic inflammation. The finding that epithelial podoplanin influences dermal responses suggests potential targets for treating conditions where coordinated tissue remodeling is disrupted.
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⚠️ Preprint – Noch nicht peer-reviewed
Dieser Artikel wurde noch nicht von unabhängigen Experten begutachtet. Die Ergebnisse sind vorläufig und sollten mit Vorsicht interpretiert werden.
Skin development and adaptation to inflammatory stress require keratinocytes to coordinate changes in cell behaviour with tissue organisation. Cell adhesion and the cortical cytoskeleton support the structural plasticity underlying these responses. Here, using complementary mouse models of global podoplanin deletion and conditional deletion in basal keratinocytes driven by keratin 5-Cre (K5Cre), we identify a role for the small transmembrane glycoprotein podoplanin in maintaining basal layer organisation and coordinating differentiation with barrier acquisition during development, as well as in inflammatory skin remodelling. Podoplanin expression was dynamically regulated during epidermal morphogenesis, becoming enriched in basal epithelial compartments before declining postnatally in the interfollicular epidermis. Both deletion models exhibited basal layer disorganisation, altered division orientation and increased epidermal thickness. Premature or expanded expression of differentiation markers was accompanied by delayed barrier acquisition, indicating that podoplanin loss uncouples differentiation marker expression from functional maturation. Barrier function subsequently recovered despite persistent histological abnormalities. In primary keratinocytes, podoplanin deficiency disrupted junctional actin organisation, reduced ERM phosphorylation and impaired junctional enrichment of pERM and doubly phosphorylated myosin light chain 2 (ppMLC2), despite largely preserved recruitment of adhesion proteins. In adult skin, K5Cre-mediated deletion altered differentiation marker dynamics following topical application of the proinflammatory agent 12-O-tetradecanoylphorbol-13-acetate (TPA), while the epidermal thickening response remained largely comparable to controls. These epidermal changes were accompanied by altered dermal thickness dynamics and an absence of TPA-induced podoplanin expression in dermal fibroblasts. Furthermore, TPA reduced the number of BrdU-retaining cells in the interfollicular epidermis of controls but not K5Cre-mediated conditional podoplanin knockout mice. This difference is consistent with impaired activation or mobilisation of slow-cycling cells, suggesting altered responsiveness within the epidermal stem and progenitor compartment. Together, these findings establish keratinocyte-expressed podoplanin as a regulator of epidermal organisation and functional maturation, with effects extending beyond the epithelium to shape the dermal response to inflammatory challenge.