Lrig1 and Wnt dependent niches dictate segregation of resident immune cells and melanocytes in murine tail epidermis

The barrier-forming, self-renewing mammalian epidermis comprises keratinocytes, pigment-producing melanocytes, and resident immune cells as first-line host defense. In murine tail skin, interfollicular epidermis patterns into pigmented ′scale′ and non-pigmented ′interscale′ epidermis. Why and how mature melanocytes confine to scale epidermis is unresolved. Here, we delineate a cellular hierarchy among epidermal cell types that determines skin patterning. Already during postnatal development, melanocytes co-segregate with newly forming scale compartments. Intriguingly, this process coincides with partitioning of both Langerhans cells and dendritic epidermal T-cells to interscale epidermis, suggesting functional segregation of pigmentation and immune surveillance. Analysis of non-pigmented mice and of mice lacking melanocytes or resident immune cells revealed that immunocyte patterning is melanocyte- and melanin-independent, and, vice versa, immune cells do not control melanocyte localization. Instead, genetically enforced progressive scale fusion upon Lrig1 deletion showed that melanocytes and immune cells dynamically follow epithelial scale:interscale patterns. Importantly, disrupting Wnt-Lef1 function in keratinocytes caused melanocyte mislocalization to interscale epidermis, implicating canonical Wnt signaling in organizing the pigmentation pattern. Together, this work uncovered cellular and molecular principles underlying the compartmentalization of tissue functions in skin.

Crosstalk with keratinocytes causes GNAQ oncogene specificity in melanoma

Different melanoma subtypes exhibit specific and non-overlapping sets of oncogene and tumor suppressor mutations, despite a common cell of origin in melanocytes. For example, activation of the Gαq/11 signaling pathway is a characteristic initiating event in primary melanomas that arise in the dermis, uveal tract or central nervous system. It is rare in melanomas arising in the epidermis. The mechanism for this specificity is unknown. Here, we present evidence that in the mouse, crosstalk with the epidermal microenvironment actively impairs the survival of melanocytes expressing the GNAQQ209L oncogene. We found that GNAQQ209L, in combination with signaling from the interfollicular epidermis (IFE), stimulates dendrite extension, leads to actin cytoskeleton disorganization, inhibits proliferation and promotes apoptosis in melanocytes. The effect was reversible and paracrine. In contrast, the epidermal environment increased the survival of wildtype and BrafV600E expressing melanocytes. Hence, our studies reveal the flip side of Gaq/11 signaling, which was hitherto unsuspected. In the future, the identification of the epidermal signals that restrain the GNAQQ209L oncogene could suggest novel therapies for GNAQ and GNA11 mutant melanomas.

Follicular Dowling-Degos Disease with Hidradenitis Suppurativa: A Case Report and Review of the Literature

Dowling-Degos disease (DDD) is an autosomal dominant disorder with variable phenotypic expression. Classically, DDD is characterized by progressive reticulate hyperpigmentation on flexures with perioral pitted scars and comedone-like hyperkeratotic papules. Follicular DDD is a rare variant which was introduced by Singh et al. [<i>Indian J Dermatol Venereol Leprol</i>. 2013 Nov–Dec;79(6):802–4]. Follicular DDD differs from other variants because of its notable comedone-like hyperkeratotic hyperpigmented papules and a distinct histopathology which demonstrates pigmented filiform and branching rete pegs originating at the follicular infundibulum with many epidermal horn cysts while the interfollicular epidermis is essentially normal. Hereby, we present a case of follicular DDD with hidradenitis suppurativa (HS). A 37-year-old Thai man presented with slowly progressive hyperpigmented comedone-like papules on the face, neck, axillae, upper trunk, and buttocks with perioral pitted scars. Punch biopsy from a comedonal lesion on his back was consistent with follicular DDD. He also had recurrent painful nodules and abscess on the back, groin, and buttock which matched the clinical criteria for the diagnosis of HS. To date, a paucity of concurrent DDD with HS has been reported. Recent genetic studies speculate a shared pathophysiologic mechanism of DDD and HS.

Micro-Injury Induces Hair Regeneration and Vitiligo Repigmentation Through Wnt/ β-Catenin Pathway

Background: Extrinsic injury can evoke intrinsic stimulation subquently initiate physiological repair process. Several kinds of injury have been studied to promote hair growth and skin pigmentation. In this study, we ask if proper injury could be employed to create local stimuli subsquently to induce hair regeneration and vitiligo repigmentation.Methods: We firstly manufactured a novel designed device to precisely control all micro-injury parameters. Then the most appropriate micro-injury extent was evaluated without over-damage to skin. The effects of micro-injury on hair regeneration and vitiligo repigmentation were examined by macroscopical observation, histological staining, gene and protein expression analysis.Results: We discover that proper micro-injury effectively induces hair regeneration by activating the hair follicle stem cell proliferation and migration downwards to hair matrix, finally shifting the hair follicle stage from telogen into anagen. On vitiligo model mice, micro-injury also induces the hair follicle melanocyte stem cell migrate upwards to interfollicular epidermis, activate and give rise to melanocytes to repopulate vitiligo lesion. Mechanism analysis indicates that the canonical Wnt/b-catenin pathway plays a key role in the micro-injury induced regeneration process. Conclusions: The present study demonstrates that micro-injury has great potential in inducing hair regeneration and vitiligo repigmentation, laid a foundation to develop micro-injury based treatment method in alopecia and vitiligo.

Epigenomic profiling of stem cells within the pilosebaceous unit identifies PRDM16 as a regulator of sebaceous gland homeostasis

The epidermis consists of different compartments such as the hair follicle (HF), sebaceous gland (SG) and interfollicular epidermis (IFE), each containing distinct stem cell (SC) populations. However, with the exception of the SCs residing within the HF bulge, other epidermal SC populations remain less well understood. Here we used an epigenomic strategy that combines H3K27me3 ChIP-seq and RNA-seq profiling to identify major regulators of pilosebaceous unit (PSU) SC located outside the bulge. When applied to the bulk of PSU SC isolated from mouse skin our approach identified both previously known and potentially novel non-bulge PSU SC regulators. Among the latter, we found that PRDM16 was predominantly enriched within the Junctional Zone (JZ), which harbors SC that contribute to renewal of the upper HF and the SG. To investigate PRDM16 function in the PSU SC, we generated an epidermal-specific Prdm16 Knock-out mouse model (K14-Cre-Prdm16fl/fl). Notably, SG homeostasis was disturbed upon loss of PRDM16 resulting in enlarged SGs, and excessive sebum production, resembling some of the features associated with human acne and sebaceous hyperplasia. Importantly, PRDM16 is essential to shut down proliferation in differentiating sebocytes. Overall, our study provides a list of putative novel regulators of PSU SC outside the bulge and identifies PRDM16 as a major regulator of SG homeostasis.

Development and Maintenance of Epidermal Stem Cells in Skin Adnexa

The skin surface is modified by numerous appendages. These structures arise from epithelial stem cells (SCs) through the induction of epidermal placodes as a result of local signalling interplay with mesenchymal cells based on the Wnt–(Dkk4)–Eda–Shh cascade. Slight modifications of the cascade, with the participation of antagonistic signalling, decide whether multipotent epidermal SCs develop in interfollicular epidermis, scales, hair/feather follicles, nails or skin glands. This review describes the roles of epidermal SCs in the development of skin adnexa and interfollicular epidermis, as well as their maintenance. Each skin structure arises from distinct pools of epidermal SCs that are harboured in specific but different niches that control SC behaviour. Such relationships explain differences in marker and gene expression patterns between particular SC subsets. The activity of well-compartmentalized epidermal SCs is orchestrated with that of other skin cells not only along the hair cycle but also in the course of skin regeneration following injury. This review highlights several membrane markers, cytoplasmic proteins and transcription factors associated with epidermal SCs.

Transcriptome Profiling and Differential Gene Expression in Canine Microdissected Anagen and Telogen Hair Follicles and Interfollicular Epidermis

The transcriptome profile and differential gene expression in telogen and late anagen microdissected hair follicles and the interfollicular epidermis of healthy dogs was investigated by using RNAseq. The genes with the highest expression levels in each group were identified and genes known from studies in other species to be associated with structure and function of hair follicles and epidermis were evaluated. Transcriptome profiling revealed that late anagen follicles expressed mainly keratins and telogen follicles expressed GSN and KRT15. The interfollicular epidermis expressed predominately genes encoding for proteins associated with differentiation. All sample groups express genes encoding for proteins involved in cellular growth and signal transduction. The expression pattern of skin-associated genes in dogs is similar to humans. Differences in expression compared to mice and humans include BMP2 expression mainly in telogen and high KRT17 expression in the interfollicular epidermis of dogs. Our data provide the basis for the investigation of the structure and function of canine skin or skin disease and support the use of dogs as a model for human cutaneous disease by assigning gene expression to specific tissue states.

Atypical Presentation of Lichen Planopilaris: Presentation of Two Cases and Review

Lichen Planopilaris (LPP) is an uncommon scalp disorder of unknown etiology and prevalence. It is thought to be an autoimmune process triggered by unknown genetic and/or environmental factors that attack hair follicles of the scalp. LPP has been reported to mimic or present in association with various autoimmune diseases and immunomodulatory therapies. We present two atypical case of LPP in Caucasian patients; the first is a patient with generalized pruritus, skin eruptions, and scalp hair loss. Biopsy of the lesions revealed exocytosis of atypical lymphocytes at the Dermo-Epidermal Junction (DEJ) and formation of small Pautrier’s microabscesses in the interfollicular epidermis as well as a robust lymphocytic inflammatory infiltrate with destruction of perifollicular appendages. This led us to the diagnosis of LPP-like Folliculotropic Mycosis Fungoides (FMF). The second case is a patient with a history of Systemic Lupus Erythematosus (SLE) who presented clinically with perifollicular erythema and alopecic patches, with loss of follicular ostia on the frontal and vertex scalp and evidence of follicular tufting. Histologically, she had decreased number of follicles with a peri-infundibular lymphocytic infiltrate and vacuolization at the Dermoepidermal Junction (DEJ) and there was also thickening of the basement membrane highlighted with a periodic acidic Schiff stain. This led to a diagnosis of SLE/LPP overlap. Keywords: Lichen Planopilaris (LPP); Cicatricial; Alopecia; Frontal Fibrosing Alopecia (FFA), Folliculotropic Mycosis Fungoides (FMF), Lichen Planus (LP).