The development of hair follicles and nail.

The hair follicle and nail unit develop and regenerate through epithelial-mesenchymal interactions. Here, we review some of the key signals and molecular interactions that regulate mammalian hair follicle and nail formation during embryonic development and how these interactions are reutilized to promote their regeneration during adult homeostasis and in response to skin wounding. Finally, we highlight the role of some of these signals in mediating human hair follicle and nail conditions.

Cell differentiation in the embryonic periderm and in scaffolding epithelia of skin appendages.

Terminal differentiation of epithelial cells is critical for the barrier function of the skin, the growth of skin appendages, such as hair and nails, and the development of the skin of amniotes. Here, we present the hypothesis that the differentiation of cells in the embryonic periderm shares characteristic features with the differentiation of epithelial cells that support the morphogenesis of cornified skin appendages during postnatal life. The periderm prevents aberrant fusion of adjacent epithelial sites during early skin development. It is shed off when keratinocytes of the epidermis form the cornified layer, the stratum corneum. A similar role is played by epithelia that ensheath cornifying skin appendages until they disintegrate to allow the separation of the mature part of the skin appendage from the adjacent tissue. These epithelia, exemplified by the inner root sheath of hair follicles and the epithelia close to the free edge of nails or claws, are referred to as scaffolding epithelia. The periderm and scaffolding epithelia are similar with regard to their transient functions in separating tissues and the conserved expression of trichohyalin and trichohyalin-like genes in mammals and birds. Thus, we propose that parts of the peridermal differentiation program were coopted to a new postnatal function during the evolution of cornified skin appendages in amniotes.

Dysembryogenetic Pathogenesis of Basal Cell Carcinoma: The Evidence to Date.

The Basal Cell Carcinoma (BCC) is a sort of unique tumour due to its combined peculiar histological features and clinical behaviour, such as the constant binary involvement of the epithelium and the stroma, the virtual absence of metastases and the predilection of specific anatomical sites for both onset and spread. A potential correlation between the onset of BCC and a dysembryogenetic process has long been hypothesised. A selective investigation of PubMed-indexed publications supporting this theory retrieved 64 selected articles published between 1901 and 2024. From our analysis of the literature review, five main research domains on the dysembryogenetic pathogenesis of BCC were identified: (1) The correlation between the topographic distribution of BCC and the macroscopic embryology, (2) the correlation between BCC and the microscopic embryology, (3) the genetic BCC, (4) the correlation between BCC and the hair follicle and (5) the correlation between BCC and the molecular embryology with a specific focus on the Hedgehog signalling pathway. A large amount of data from microscopic and molecular research consistently supports the hypothesis of a dysembryogenetic pathogenesis of BCC. Such evidence is promoting advances in the clinical management of this disease, with innovative targeted molecular therapies on an immune modulating basis being developed.

Evaluating Planar Cell Polarity in the Developing Mouse Epidermis.

Epidermal tissues are among the most striking examples of planar polarity. Insect bristles, fish scales, and mammalian fur are all uniformly oriented along an animal's body axis. The collective alignment of epidermal structures provides a valuable system to interrogate the signaling mechanisms that coordinate cellular behaviors at both local and tissue-levels. Here, we provide methods to analyze the planar organization of hair follicles within the mouse epidermis. Hair follicles are specified and bud into the underlying dermis during embryonic development. Shortly after, follicle cells dynamically rearrange to orient each follicle toward the anterior of the animal. When directional signaling is disrupted, hair follicles become misoriented. In this chapter, we describe how to create a spatial map of hair follicle orientations to reveal tissue-scale patterns in both embryonic and postnatal skin. Additionally, we provide a live imaging protocol that can be used to monitor cell movements in embryonic skin explants to reveal the cellular behaviors that polarize the hair follicle itself.

Integrating Single-Cell and Spatial Transcriptomics Reveals Heterogeneity of Early Pig Skin Development and a Subpopulation with Hair Placode Formation.

The dermis and epidermis, crucial structural layers of the skin, encompass appendages, hair follicles (HFs), and intricate cellular heterogeneity. However, an integrated spatiotemporal transcriptomic atlas of embryonic skin has not yet been described and would be invaluable for studying skin-related diseases in humans. Here, single-cell and spatial transcriptomic analyses are performed on skin samples of normal and hairless fetal pigs across four developmental periods. The cross-species comparison of skin cells illustrated that the pig epidermis is more representative of the human epidermis than mice epidermis. Moreover, Phenome-wide association study analysis revealed that the conserved genes between pigs and humans are strongly associated with human skin-related diseases. In the epidermis, two lineage differentiation trajectories describe hair follicle (HF) morphogenesis and epidermal development. By comparing normal and hairless fetal pigs, it is found that the hair placode (Pc), the most characteristic initial structure in HFs, arises from progenitor-like OGN+/UCHL1+ cells. These progenitors appear earlier in development than the previously described early Pc cells and exhibit abnormal proliferation and migration during differentiation in hairless pigs. The study provides a valuable resource for in-depth insights into HF development, which may serve as a key reference atlas for studying human skin disease etiology using porcine models.

Stabilization of Epithelial ß-Catenin Compromises Mammary Cell Fate Acquisition and Branching Morphogenesis.

The Wnt/ß-catenin pathway plays a critical role in cell fate specification, morphogenesis, and stem cell activation across diverse tissues, including the skin. In mammals, the embryonic surface epithelium gives rise to the epidermis as well as the associated appendages including hair follicles and mammary glands, both of which depend on epithelial Wnt/ß-catenin activity for initiation of their development. Later on, Wnts are thought to enhance mammary gland growth and branching, whereas in hair follicles, they are essential for hair shaft formation. In this study, we report a strong downregulation of epithelial Wnt/ß-catenin activity as the mammary bud progresses to branching. We show that forced activation of epithelial ß-catenin severely compromises embryonic mammary gland branching. However, the phenotype of conditional Lef1-deficient embryos implies that a low level of Wnt/ß-catenin activity is necessary for mammary cell survival. Transcriptomic profiling suggests that sustained high ß-catenin activity leads to maintenance of mammary bud gene signature at the expense of outgrowth/branching gene signature. In addition, it leads to upregulation of epidermal differentiation genes. Strikingly, we find a partial switch to hair follicle fate early on upon stabilization of ß-catenin, suggesting that the level of epithelial Wnt/ß-catenin signaling activity may contribute to the choice between skin appendage identities.

Stem cells in embryonic skin development

The skin is a complex stratified organ which acts not only as a permeability barrier and defense against external agents, but also has essential thermoregulatory, sensory and metabolic functions. Due to its high versatility and activity, the skin undergoes continuous self-renewal to repair damaged tissue and replace old cells. Consequently, the skin is a reservoir for adult stem cells of different embryonic origins. Skin stem cell populations reside in the adult hair follicle, sebaceous gland, dermis and epidermis. However, the origin of most of the stem cell populations found in the adult epidermis is still unknown. Far more unknown is the embryonic origin of other stem cells that populate the other layers of this tissue. In this review we attempt to clarify the emergence, structure, markers and embryonic development of diverse populations of stem cells from the epidermis, dermis and related appendages such as the sebaceous gland and hair follicle.