Probes for INS

Fibroblasts are the main cell type in the dermis. They are responsible for the synthesis and deposition of structural proteins such as collagen and elastin, which are integrated into the extracellular matrix (ECM). Mouse and human studies using flow cytometry, cell culture, skin reconstitution, and lineage tracing experiments have shown the existence of different subpopulations of fibroblasts, including papillary fibroblasts, reticular fibroblasts, and fibroblasts comprising the dermal papilla at the base of the hair follicle. In recent years, the technological advances in single-cell sequencing have allowed researchers to study the repertoire of cells present in full-thickness skin including the dermis. Multiple groups have confirmed that distinct fibroblast populations can be identified in mouse and human dermis on the basis of differences in the transcriptional profile. Here, we discuss the current state of knowledge regarding dermal fibroblast heterogeneity in healthy mouse and human skin, highlighting the similarities and differences between mouse and human fibroblast subpopulations. We also discuss how fibroblast heterogeneity may provide insights into physiological wound healing and its dysfunction in pathological states such as hypertrophic and keloid scars.

The development of multi-omic profiling tools has rapidly expanded in recent years, along with their use in profiling skin tissues in various contexts, including dermatologic diseases. Among these tools, single-cell RNA-sequencing (scRNA-seq) and spatial transcriptomics (ST) have emerged as widely adopted and powerful assays for elucidating key cellular components and their spatial arrangement within skin disease. Here, we review recent biological insights gained from the use of scRNA-seq and ST, and the advantages of combining both, for profiling skin disease, including aberrant wound healing, inflammatory skin diseases, and cancer. We discuss the role of scRNA-seq and ST for improving skin disease treatments and moving towards the goal of achieving precision medicine in dermatology, whereby patients can be optimally matched to treatments that maximize therapeutic response.

Dupilumab has revolutionized the treatment of atopic dermatitis. However, not all patients respond optimally, and this may relate to underlying molecular heterogeneity. Nevertheless, clinically useful and accessible methods to assess such heterogeneity have not been developed.We assessed whether cytokine staining and/or histologic features correlate with clinical response to dupilumab in patients with eczematous dermatitis.We retrospectively analyzed biopsies from 61 patients with eczematous dermatitis treated with dupilumab (90.2% met Hanifin-Rajka criteria for atopic dermatitis). RNA in situ hybridization was used to measure markers of type 2 (interleukin [IL]4, IL13), type 1 (interferon gamma) and type 3 (IL17A, IL17F, IL22) inflammation. Histologic features were also assessed. Patterns were compared among complete (n = 16), partial (n = 37), and nonresponders (n = 8) to dupilumab.We found that increased IL13 expression was associated with optimal response to dupilumab. In contrast, nonresponders tended to express less IL13 and relatively greater levels of type 1 and 3 cytokines. In addition, certain histologic features tended to correlate with improved response to dupilumab.Retrospective approach and small size of the nonresponder group.Cytokine RNA in situ hybridization may aid in treatment selection for eczematous disorders. Moreover, personalization of treatment selection for inflammatory skin diseases may be possible.

Basaloid follicular hamartomas (BFH) are benign small basaloid skin tumors that can present as solitary or multiple lesions. Congenital BFH lesions arranged in a segmental distribution have been described, suggesting they derive from a somatic post-zygotic mutational event. Previously, BFH were described in Happle-Tinschert syndrome, which results from a post-zygotic SMO variant and is characterized by segmental BFH with variable involvement of the teeth, skeleton, and central nervous system. Here, we describe two patients with isolated segmental BFH and no systemic involvement. Paired whole exome sequencing of BFH and normal tissue revealed a pathogenic SMO c.1234 C>T, p.L412F variant restricted to BFH tissue. We characterized the proliferation index and expression of Hedgehog and Wnt/beta-catenin pathway related proteins in segmental BFH compared to sporadic basal cell carcinomas (BCCs) and found that segmental BFH had a lower proliferation index. Although segmental BFH expressed a similar level of Gli-1 compared to BCCs, levels of LEF-1 and SOX-9 expression in BFH were weaker for both and patchier for LEF-1. Our results show that a somatic SMO activating variant causes segmental BFH. Since these patients are prone to developing BCCs, differences in SOX9, LEF1, and Ki-67 expression can help distinguish between these two basaloid lesions.

Sensory neurons innervating the skin are conventionally thought to be the sole transducers of 3 touch, temperature, pain, and itch. However, recent studies have shown that keratinocytes - like 4 Merkel cells - act as sensory transducers, whether for innocuous or noxious mechanical, thermal, 5 or chemical stimuli and communicate with intra-epidermal free nerve endings via chemical 6 synaptic contacts. This paradigm shift leads to the consideration of the whole epidermis as a 7 sensory epithelium. Sensory neurons additionally function as an efferent system. Through the 8 release of neuropeptides in intimate neuro-epidermal contact areas, they contribute to epidermal 9 homeostasis and to the pathogenesis of inflammatory skin diseases. To counteract the dogma 10 regarding neuro-cutaneous interactions, seen exclusively from the perspective of soluble and 11 spreading mediators, this review highlights the essential contribution of the unrecognized 12 anatomical contacts between the sensory neurons and the epidermal cells (keratinocytes, 13 melanocytes, Langerhans cells, and Merkel cells) which serve the reciprocal dialogue between 14 the skin, nervous system, and immune system.