Anatomically distinct fibroblast subsets determine skin autoimmune patterns.

The skin serves as a physical barrier and an immunological interface that protects the body from the external environment1-3. Aberrant activation of immune cells can induce common skin autoimmune diseases such as vitiligo, which are often characterized by bilateral symmetric lesions in certain anatomic regions of the body4-6. Understanding what orchestrates the activities of cutaneous immune cells at an organ level is necessary for the treatment of autoimmune diseases. Here we identify subsets of dermal fibroblasts that are responsible for driving patterned autoimmune activity, by using a robust mouse model of vitiligo that is based on the activation of endogenous auto-reactive CD8+ T cells that target epidermal melanocytes. Using a combination of single-cell analysis of skin samples from patients with vitiligo, cell-type-specific genetic knockouts and engraftment experiments, we find that among multiple interferon-γ (IFNγ)-responsive cell types in vitiligo-affected skin, dermal fibroblasts are uniquely required to recruit and activate CD8+ cytotoxic T cells through secreted chemokines. Anatomically distinct human dermal fibroblasts exhibit intrinsic differences in the expression of chemokines in response to IFNγ. In mouse models of vitiligo, regional IFNγ-resistant fibroblasts determine the autoimmune pattern of depigmentation in the skin. Our study identifies anatomically distinct fibroblasts with permissive or repressive IFNγ responses as the key determinant of body-level patterns of lesions in vitiligo, and highlights mesenchymal subpopulations as therapeutic targets for treating autoimmune diseases.

Hair shaft miniaturization causes stem cell depletion through mechanosensory signals mediated by a Piezo1-calcium-TNF-α axis.

In aging, androgenic alopecia, and genetic hypotrichosis disorders, hair shaft miniaturization is often associated with hair follicle stem cell (HFSC) loss. However, the mechanism causing this stem cell depletion in vivo remains elusive. Here we show that hair shaft loss or a reduction in diameter shrinks the physical niche size, which results in mechanical compression of HFSCs and their apoptotic loss. Mechanistically, cell compression activates the mechanosensitive channel Piezo1, which triggers calcium influx. This confers tumor necrosis factor alpha (TNF-α) sensitivity in a hair-cycle-dependent manner in otherwise resistant HFSCs and induces ectopic apoptosis. Persistent hair shaft miniaturization during aging and genetic hypotrichosis disorders causes long-term HFSC loss by inducing continuous ectopic apoptosis through Piezo1. Our results identify an unconventional role of the inert hair shaft structure as a functional niche component governing HFSC survival and reveal a mechanosensory axis that regulates physical-niche-atrophy-induced stem cell depletion in vivo.

Hair follicle stem cells regulate retinoid metabolism to maintain the self-renewal niche for melanocyte stem cells.

Metabolites are major biological parameters sensed by many cell types in vivo, whether they function as signaling mediators of SC and niche cross talk to regulate tissue regeneration is largely unknown. We show here that deletion of the Notch pathway co-factor RBP-J specifically in mouse HFSCs triggers adjacent McSCs to precociously differentiate in their shared niche. Transcriptome screen and in vivo functional studies revealed that the elevated level of retinoic acid (RA) caused by de-repression of RA metabolic process genes as a result of RBP-J deletion in HFSCs triggers ectopic McSCs differentiation in the niche. Mechanistically the increased level of RA sensitizes McSCs to differentiation signal KIT-ligand by increasing its c-Kit receptor protein level in vivo. Using genetic approach, we further pinpointed HFSCs as the source of KIT-ligand in the niche. We discover that HFSCs regulate the metabolite RA level in vivo to allow self-renewal of neighboring McSCs.

Hoxc-Dependent Mesenchymal Niche Heterogeneity Drives Regional Hair Follicle Regeneration.

Mesenchymal niche cells instruct activity of tissue-resident stem and progenitor cell populations. Epithelial stem cells in hair follicles (HFs) have region-specific activity, which may arise from intrinsic cellular heterogeneity within mesenchymal dermal papilla (DP) cells. Here we show that expression of Hoxc genes is sufficient to reprogram mesenchymal DP cells and alter the regenerative potential of epithelial stem cells. Hoxc gene expression in adult skin dermis closely correlates with regional HF regeneration patterns. Disrupting the region-specific expression patterns of Hoxc genes, by either decreasing their epigenetic repression via Bmi1 loss or inducing ectopic interactions of the Hoxc locus with an active epigenetic region, leads to precocious HF regeneration. We further show that a single Hoxc gene is sufficient to activate dormant DP niches and promote regional HF regeneration through canonical Wnt signaling. Altogether, these results reveal that Hoxc genes bestow mesenchymal niches with tissue-level heterogeneity and plasticity.

The complete mitochondrial genome of the color changeable toad-headed agama, Phrynocephalus versicolor (Reptilia, Squamata, Agamidae).

The complete mitochondrial genome sequence of color changeable toad-headed agama, Phrynocephalus versicolor, was determined using polymerase chain reaction (PCR), long-and-accurate PCR and directly sequencing by primer walking. The entire mitochondrial genome of P. versicolor was 16,429 bp in length, the accession was KJ749841 and the content of A, T, C, and G were 36.1%, 26.5%, 24.9% and 12.5%, respectively, which was similar to most vertebrate. The complete mitochondrial genome of P. versicolor contain 13 protein-coding genes, 2 rRNA genes, 23 tRNA genes, plus one control region and was similar to those of other Phrynocephalus sand lizards in gene arrangement and composition, except that tRNA-Phe and tRNA-Pro were exchanged and tRNA-Phe had two copies. The control region comprised three parts, one between tRNA-Thr and tRNA-Phe, a second between tRNA-Pro and tRNA-Phe, and a third between tRNA-Phe and 12S RNA. The complete mitochondrial genome of P. versicolor provided fundamental data for resolving phylogenetic relationship problems related to Agaimidae and genus Phrynocephalus.

Embryonic attenuated Wnt/ß-catenin signaling defines niche location and long-term stem cell fate in hair follicle.

Long-term adult stem cells sustain tissue regeneration throughout the lifetime of an organism. They were hypothesized to originate from embryonic progenitor cells that acquire long-term self-renewal ability and multipotency at the end of organogenesis. The process through which this is achieved often remains unclear. Here, we discovered that long-term hair follicle stem cells arise from embryonic progenitor cells occupying a niche location that is defined by attenuated Wnt/ß-catenin signaling. Hair follicle initiation is marked by placode formation, which depends on the activation of Wnt/ß-catenin signaling. Soon afterwards, a region with attenuated Wnt/ß-catenin signaling emerges in the upper follicle. Embryonic progenitor cells residing in this region gain expression of adult stem cell markers and become definitive long-term hair follicle stem cells at the end of organogenesis. Attenuation of Wnt/ß-catenin signaling is a prerequisite for hair follicle stem cell specification because it suppresses Sox9, which is required for stem cell formation.