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Human prenatal skin is populated by innate immune cells, including macrophages, but whether they act solely in immunity or have additional functions in morphogenesis is unclear. Here we assembled a comprehensive multi-omics reference atlas of prenatal human skin (7–17 post-conception weeks), combining single-cell and spatial transcriptomics data, to characterize the microanatomical tissue niches of the skin. This atlas revealed that crosstalk between non-immune and immune cells underpins the formation of hair follicles, is implicated in scarless wound healing and is crucial for skin angiogenesis. We systematically compared a hair-bearing skin organoid (SkO) model derived from human embryonic stem cells and induced pluripotent stem cells to prenatal and adult skin 1 . The SkO model closely recapitulated in vivo skin epidermal and dermal cell types during hair follicle development and expression of genes implicated in the pathogenesis of genetic hair and skin disorders. However, the SkO model lacked immune cells and had markedly reduced endothelial cell heterogeneity and quantity. Our in vivo prenatal skin cell atlas indicated that macrophages and macrophage-derived growth factors have a role in driving endothelial development. Indeed, vascular network remodelling was enhanced following transfer of autologous macrophages derived from induced pluripotent stem cells into SkO cultures. Innate immune cells are therefore key players in skin morphogenesis beyond their conventional role in immunity, a function they achieve through crosstalk with non-immune cells. A comprehensive multi-omics reference atlas of prenatal human skin shows that innate immune cells crosstalk with non-immune cells to perform pivotal roles in skin morphogenesis, including the formation of hair follicles.

Understanding global communications among cells requires accurate representation of cell-cell signaling links and effective systems-level analyses of those links. We construct a database of interactions among ligands, receptors and their cofactors that accurately represent known heteromeric molecular complexes. We then develop CellChat, a tool that is able to quantitatively infer and analyze intercellular communication networks from single-cell RNA-sequencing (scRNA-seq) data. CellChat predicts major signaling inputs and outputs for cells and how those cells and signals coordinate for functions using network analysis and pattern recognition approaches. Through manifold learning and quantitative contrasts, CellChat classifies signaling pathways and delineates conserved and context-specific pathways across different datasets. Applying CellChat to mouse and human skin datasets shows its ability to extract complex signaling patterns. Our versatile and easy-to-use toolkit CellChat and a web-based Explorer ( http://www.cellchat.org/ ) will help discover novel intercellular communications and build cell-cell communication atlases in diverse tissues. Single-cell methods record molecule expressions of cells in a given tissue, but understanding interactions between cells remains challenging. Here the authors show by applying systems biology and machine learning approaches that they can infer and analyze cell-cell communication networks in an easily interpretable way.

Fibroblasts constitute the major mesenchymal cell type in the connective tissue and their functions are remarkably diverse: here, by characterising lineages of mouse skin fibroblasts, it is shown that distinct subpopulations contribute to skin development and repair during injury. Two fibroblast lineages in skin development and repair Fibroblasts are unremarkable looking cells found in most tissues in the body, where they are mainly concerned with making the collagen that supports other cell types. The cells all look much the same yet are functionally diverse, prompting the question, is there just one cell type responding differently to different stimuli, or do individual cells specialize? A transplantation and lineage tracing study in mice now shows that skin connective tissue arises from two distinct fibroblast lineages that also contribute differentially to skin development and repair after injury. One cell type forms the lower dermis and the other the upper dermis. The latter lineage is required for hair follicle production. In wounded adult skin, the initial wave of dermal repair is mediated by the 'lower' lineage, which may explain the absence of hair follicles in newly closed wounds. The authors develop a comprehensive lineage tree for all fibroblast-derived cell types in mouse dermis, including smooth muscle cells and adipocytes. Fibroblasts are the major mesenchymal cell type in connective tissue and deposit the collagen and elastic fibres of the extracellular matrix (ECM) 1 . Even within a single tissue, fibroblasts exhibit considerable functional diversity, but it is not known whether this reflects the existence of a differentiation hierarchy or is a response to different environmental factors. Here we show, using transplantation assays and lineage tracing in mice, that the fibroblasts of skin connective tissue arise from two distinct lineages. One forms the upper dermis, including the dermal papilla that regulates hair growth and the arrector pili muscle, which controls piloerection. The other forms the lower dermis, including the reticular fibroblasts that synthesize the bulk of the fibrillar ECM, and the preadipocytes and adipocytes of the hypodermis. The upper lineage is required for hair follicle formation. In wounded adult skin, the initial wave of dermal repair is mediated by the lower lineage and upper dermal fibroblasts are recruited only during re-epithelialization. Epidermal β-catenin activation stimulates the expansion of the upper dermal lineage, rendering wounds permissive for hair follicle formation. Our findings explain why wounding is linked to formation of ECM-rich scar tissue that lacks hair follicles 2 , 3 , 4 . They also form a platform for discovering fibroblast lineages in other tissues and for examining fibroblast changes in ageing and disease.

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.

Two theories address the origin of repeating patterns, such as hair follicles, limb digits, and intestinal villi, during development. The Turing reaction-diffusion system posits that interacting diffusible signals produced by static cells first define a prepattern that then induces cell rearrangements to produce an anatomical structure. The second theory, that of mesenchymal self-organisation, proposes that mobile cells can form periodic patterns of cell aggregates directly, without reference to any prepattern. Early hair follicle development is characterised by the rapid appearance of periodic arrangements of altered gene expression in the epidermis and prominent clustering of the adjacent dermal mesenchymal cells. We assess the contributions and interplay between reaction-diffusion and mesenchymal self-organisation processes in hair follicle patterning, identifying a network of fibroblast growth factor (FGF), wingless-related integration site (WNT), and bone morphogenetic protein (BMP) signalling interactions capable of spontaneously producing a periodic pattern. Using time-lapse imaging, we find that mesenchymal cell condensation at hair follicles is locally directed by an epidermal prepattern. However, imposing this prepattern's condition of high FGF and low BMP activity across the entire skin reveals a latent dermal capacity to undergo spatially patterned self-organisation in the absence of epithelial direction. This mesenchymal self-organisation relies on restricted transforming growth factor (TGF) β signalling, which serves to drive chemotactic mesenchymal patterning when reaction-diffusion patterning is suppressed, but, in normal conditions, facilitates cell movement to locally prepatterned sources of FGF. This work illustrates a hierarchy of periodic patterning modes operating in organogenesis.

Here, we review melanocyte development and how the embryonic melanoblast, although specified to become a melanocyte, is prone to cellular plasticity and is not fully committed to the melanocyte lineage. Even fully differentiated and pigment-producing melanocytes do not always have a stable phenotype. The gradual lineage restriction of neural crest cells toward the melanocyte lineage is determined by both cell-intrinsic and extracellular signals in which differentiation and pathfinding ability reciprocally influence each other. These signals are leveraged by subtle differences in timing and axial positioning. The most extensively studied migration route is the dorsolateral path between the dermomyotome and the prospective epidermis, restricted to melanoblasts. In addition, the embryonic origin of the skin dermis through which neural crest derivatives migrate may also affect the segregation between melanogenic and neurogenic cells in embryos. It is widely accepted that, irrespective of the model organism studied, the immediate precursor of both melanoblast and neurogenic populations is a glial-melanogenic bipotent progenitor. Upon exposure to different conditions, melanoblasts may differentiate into other neural crest-derived lineages such as neuronal cells and vice versa. Key factors that regulate melanoblast migration and patterning will regulate melanocyte homeostasis during different stages of hair cycling in postnatal hair follicles.

Multiciliate cells function prominently in the respiratory system, brain ependyma and female reproductive tract to produce vigorous fluid flow along epithelial surfaces. These specialized cells form during development when epithelial progenitors undergo an unusual form of ciliogenesis, in which they assemble and project hundreds of motile cilia. Notch inhibits multiciliate cell formation in diverse epithelia, but how progenitors overcome lateral inhibition and initiate multiciliate cell differentiation is unknown. Here we identify a coiled-coil protein, termed multicilin, which is regulated by Notch and highly expressed in developing epithelia where multiciliate cells form. Inhibiting multicilin function specifically blocks multiciliate cell formation in Xenopus skin and kidney, whereas ectopic expression induces the differentiation of multiciliate cells in ectopic locations. Multicilin localizes to the nucleus, where it directly activates the expression of genes required for multiciliate cell formation, including foxj1 and genes mediating centriole assembly. Multicilin is also necessary and sufficient to promote multiciliate cell differentiation in mouse airway epithelial cultures. These findings indicate that multicilin initiates multiciliate cell differentiation in diverse tissues, by coordinately promoting the transcriptional changes required for motile ciliogenesis and centriole assembly. Several specialized cell types assemble hundreds of motile cilia to accomplish their function. Kintner and colleagues identify the coiled-coil protein multicilin as an essential regulator of multicilia formation in Xenopus skin and the mammalian kidney. Their data indicate that multicilin activates the transcription of genes required for multicilia formation, including the transcription factor Foxj1.

The integration of basally located progenitors into an existing epithelium, termed apical emergence, is crucial for the morphogenesis and homeostasis of epithelial tissues and organs. Using Xenopus as a model system, we explore the role of intracellular calcium in apical emergence during the development of mucociliary skin epithelium. Our findings reveal that calcium transients precede the apical emergence of Multiciliated cell (MCC) progenitors and are essential for their insertion into the overlying skin epithelium. Furthermore, we demonstrate that phospholipase C (PLC) activity is required for generating calcium transients, which regulate MCC apical emergence via Calmodulin. The PLC/Ca²⁺/Calmodulin axis is necessary for the function of the apical actin network by influencing its stability. Lastly, we show that intracellular calcium regulates apical emergence in distinct basal progenitors. This study advances our understanding of the molecular mechanisms governing apical emergence and highlights the importance of calcium in coordinating cytoskeletal dynamics during epithelial morphogenesis. The integration of basally located progenitors into an existing epithelium is crucial for organ morphogenesis. Here, the authors show that phospholipase C-dependent calcium transients act via calmodulin to promote apical emergence of multiciliated cell progenitors and other progenitor types into the overlying skin epithelium in Xenopus.

Cashmere goat skin contains two types of hair follicles (HF): primary hair follicles (PHF) and secondary hair follicles (SHF). Although multiple genetic determinants associated with HF formation have been identified, the molecules that determine the independent morphogenesis of HF in cashmere goats remain elusive. The growth and development of SHF directly influence the quantity and quality of cashmere production. Here, we report the transcriptome profiling analysis of nine skin samples from cashmere goats using 60- and 120-day-old embryos (E60 and E120, respectively), as well as newborns (NB), through RNA-sequencing (RNA-seq). HF morphological changes indicated that PHF were initiated at E60, with maturation from E120, while differentiation of SHF was identified at E120 until formation of cashmere occurred after birth (NB). The RNA-sequencing analysis generated over 20.6 million clean reads from each mRNA library. The number of differentially expressed genes (DEGs) in E60 vs. E120, E120 vs. NB, and E60 vs. NB were 1,024, 0 and 1,801, respectively, indicating that no significant differences were found at transcriptomic levels between E120 and NB. Key genes including B4GALT4, TNC, a-integrin, and FGFR1, were up-regulated and expressed in HF initiation from E60 to E120, while regulatory genes such as GPRC5D, PAD3, HOXC13, PRR9, VSIG8, LRRC15, LHX2, MSX-2, and FOXN1 were up-regulated and expressed in HF keratinisation and hair shaft differentiation from E120 and NB to E60. Several genes belonging to the KRT and KRTAP gene families were detected throughout the three HF developmental stages. The transcriptional trajectory analyses of all DEGs indicated that immune privilege, glycosaminoglycan biosynthesis, extracellular matrix receptor interaction, and growth factor receptors all played dominant roles in the epithelial-mesenchymal interface and HF formation. We found that the Wnt, transforming growth factor-beta/bone morphogenetic protein, and Notch family members played vital roles in HF differentiation and maturation. The DEGs we found could be attributed to the generation and development of HF, and thus will be critically important for improving the quantity and quality of fleece production in animals for fibres.

Corn snakes are emerging models for animal colouration studies. Here, we focus on the Terrazzo morph, whose skin pattern is characterized by stripes rather than blotches. Using genome mapping, we discover a disruptive mutation in the coding region of the Premelanosome protein ( PMEL ) gene. Our transcriptomic analyses reveal that PMEL expression is significantly downregulated in Terrazzo embryonic tissues. We produce corn snake PMEL knockouts, which present a comparable colouration phenotype to Terrazzo and the subcellular structure of their melanosomes and xanthosomes is also similarly impacted. Our single-cell expression analyses of wild-type embryonic dorsal skin demonstrate that all chromatophore progenitors express PMEL at varying levels. Finally, we show that in wild-type embryos PMEL -expressing cells are initially uniformly spread before forming aggregates and eventually blotches, as seen in the adults. In Terrazzo embryos, the aggregates fail to form. Our results provide insights into the mechanisms governing colouration patterning in reptiles. Corn snakes are a useful model organism for studying skin pigmentation. Here they characterize the Terrazzo morph and identify the role of PMEL in the patterning of pigmented cells in the skin, explaining how the wild-type blotches change to stripes in Terrazzo.