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β-cateinin activation in hair follicle dermal sheath induces ectopic hair outgrowth and skin fibrosis

ABSTRACT: Dermal sheath (DS) shows potent hair inducing capability and high plasticity without leading to immuno rejection. A recent study showed a subset of DS cells, identified as hair follicle (HF) dermal stem cells, can be mobilized to regenerate DS, maintain/supply the cell number of dermal papilla (DP) and modulate hair type. However, it is unclear how Wnt/β-catenin signaling regulates DS cells behaviors. Here we report that activation of β-catenin in DS, to some extent, endows it with hair inducing ability, reprogramming HF epidermal cells to generate new outgrowth. The new formed dermal condensates (DC)/DP lying adjacent the outgrowth derives from DS and/or its progeny, and homeostasis of pre-existing HFs is disturbed. Additionally, progressive skin fibrosis is prominent in hypodermis, where the excessive activated fibroblasts at least partially originate from DS and/or its progeny. Gene expression analysis of purified DS cells revealed that 44% DC signature genes are regulated, most of which are up-regulated. We found elevated expression of several growth factors, including Noggin, Fgf7 and Fgf10, which were previously implicated in HF induction. In summary, we confirm the high plasticity of DS cells by in vivo assays and report a mechanism by which Wnt/β-catenin signaling controls DS cells behaviors.

ORGANISM(S): Mus musculus

PROVIDER: GSE81615 | GEO | 2016/05/31

SECONDARY ACCESSION(S): PRJNA322080

REPOSITORIES: GEO

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Î²-cateinin activation in hair follicle dermal sheath induces ectopic hair outgrowth and skin fibrosis

Project description:Dermal sheath (DS) shows potent hair inducing capability and high plasticity without leading to immuno rejection. A recent study showed a subset of DS cells, identified as hair follicle (HF) dermal stem cells, can be mobilized to regenerate DS, maintain/supply the cell number of dermal papilla (DP) and modulate hair type. However, it is unclear how Wnt/Î²-catenin signaling regulates DS cells behaviors. Here we report that activation of Î²-catenin in DS, to some extent, endows it with hair inducing ability, reprogramming HF epidermal cells to generate new outgrowth. The new formed dermal condensates (DC)/DP lying adjacent the outgrowth derives from DS and/or its progeny, and homeostasis of pre-existing HFs is disturbed. Additionally, progressive skin fibrosis is prominent in hypodermis, where the excessive activated fibroblasts at least partially originate from DS and/or its progeny. Gene expression analysis of purified DS cells revealed that 44% DC signature genes are regulated, most of which are up-regulated. We found elevated expression of several growth factors, including Noggin, Fgf7 and Fgf10, which were previously implicated in HF induction. In summary, we confirm the high plasticity of DS cells by in vivo assays and report a mechanism by which Wnt/Î²-catenin signaling controls DS cells behaviors. We prospectively isolated control and cÎex3 DS cells (YFP+ve CD34-ve ALP-ve ITGÎ±8-ve cells) from P15 dorsal skins by FACS.

2016-05-31 | E-GEOD-81615 | biostudies-arrayexpress

Dysfunction of hair follicle mesenchymal progenitors contributes to age related hair loss

Project description:Advanced age drives the progressive degeneration of mammalian hair follicles (HF) and termination of its regeneration cycle. The role of hair follicle dermal stem cell (hfDSC) in this age-associated HF dysfunction remains largely unexplored. Here, we first characterize a novel function of hfDSCs in regenerating the full dermal papilla (DP) after laser ablation. Next, we performed long-term fate mapping, age-dependant in vivo clonal analysis and in vitro proliferation assay on hfDSCs to describe the age-related defects in mesenchymal stem cell self-renewal and differentiation capabilities. Moreover, single-cell RNA-sequencing of the HF mesenchymal population mapped the intrinsic transcriptional changes that may drive their age-related dysfunction. We highlight the requirement of hfDSCs for normal HF regeneration. Our findings characterize a novel function of mesenchymal stem cells, and how this crucial cell becomes dysfunctional with age to drive age-related hair loss.

2020-04-20 | GSE115424 | GEO

Paracrine TGFß Signaling Counterbalances BMP-Mediated Repression in Hair Follicle Stem Cell Activation

Project description:Hair follicle (HF) regeneration begins when communication between quiescent epithelial stem cells (SCs) and underlying mesenchymal dermal papillae (DP) generates sufficient activating cues to overcome repressive BMP signals from surrounding niche cells. We uncovered a hitherto unrecognized DP transmitter, TGFβ2, which activates Smad2/3 transiently in HFSCs concomitant with entry into tissue regeneration. We used microarrays to detect the genes specifically affected by TGFß receptor II-deficient mice upon HFSC activation. Hair follicle stem cells (HFSCs) of hair gem (HG) and bulge, and total skin keratinocytes were FACS-purified from the mouse back skin at 2nd telogen-to-anagen transition stages.

2012-01-04 | E-GEOD-33471 | biostudies-arrayexpress

Signaling networks of developing hair follicles

Project description:The hair follicle (HF) is a complex miniorgan that serves as an ideal model system to study stem cell (SC) interactions with the niche during growth and regeneration. Dermal papilla (DP) cells are required for activating SCs during the adult hair cycle, but the signal exchange between niche and SC precursors/transit amplifying progenitor cells (TACs) that regulates HF morphogenetic growth is largely unknown. Here we use six transgenic reporters to isolate 14 major skin and HF cell populations. With next-generation RNA sequencing we characterize their transcriptomes and define unique molecular signatures. SC precursors, TACs and the DP niche express a plethora of known and novel ligands and receptors. Signaling interaction network analysis reveals a birds-eye view of pathways implicated in epithelial-mesenchymal interactions. Using a systematic tissue-wide approach this work provides a comprehensive platform, linked to an interactive online database, to identify and further explore the SC/TAC/niche crosstalk regulating HF growth.

2016-03-17 | GSE77197 | GEO

Expression data from human hair follicles (ex vivo) incubated with cyclosporine A and vehicle control

Project description:Since hair growth disorders can carry a major psychological burden, more effective human hair growth-modulatory agents need to be urgently developed. Here, we used the hypertrichosis-inducing immunosuppressant, cyclosporine A (CsA), as a lead compound to identify new hair growth-promoting targets. Through microarray analysis we identified the Wnt inhibitor, SFRP1, as being downregulated in the dermal papilla (DP) of CsA-treated human scalp hair follicles (HFs) ex vivo. Therefore, we further investigated the function of SFRP1 using a pharmacological approach and found that SFRP1 regulates intrafollicular canonical Wnt/β-catenin activity through inhibition of Wnt ligands in the human hair bulb. Conversely, inhibiting SFRP1 activity through the SFRP1 antagonist, WAY-316606, enhanced hair shaft production, hair shaft keratin expression and inhibited spontaneous HF regression (catagen) ex vivo. Collectively, these data (a) identify Wnt signaling as a novel, non-immune-inhibitory CsA target; (b) introduce SFRP1 as a physiologically important regulator of canonical β-catenin activity in a human (mini-)organ; and (c) demonstrate WAY-316606 to be a promising new promoter of human hair growth. Since inhibiting SFRP1 only facilitates Wnt signaling through ligands that are already present, this “ligand-limited” therapeutic strategy for promoting human hair growth may circumvent potential oncological risks associated with chronic Wnt over-activation. We used microarrays to identify novel hair growth promoting targets in human hair follicles through the use of cyclosporine A.

2018-05-09 | GSE109632 | GEO

Paracrine TGFß Signaling Counterbalances BMP-Mediated Repression in Hair Follicle Stem Cell Activation

2012-01-04 | GSE33471 | GEO

RNA-Seq of human fetal and adult scalp hair follicle dermal papilla (DP), dermal sheath cup (DSC), and interfollicular dermal (IFD) cells

Project description:Much is still unknown about the molecular regulatory networks which govern the dermal papilla’s (DP) ability to induce hair follicle regeneration, a capacity which gradually decreases with age. DP and dermal sheath cup (DSC) cells from mature, anagen phase, hair follicles were manually microdissected from fresh frozen sections of 16-18 week human fetal scalp and 30-60 year old adult male scalp. Interfollicular dermal (IFD) fibroblasts were harvested for comparison. RNA-seq libraries from each cell population were prepared with Nugen’s Ovation RNA-Seq and Ultralow Library systems, sequenced to approximately 100 million total reads. A set of 121 genes was identified as significantly upregulated in fetal DP cells, as compared to both fetal DSC and IFD populations. Wnt/β-catenin, Shh, FGF, BMP, and Notch signaling pathways were significantly enriched among those genes differentially expressed between fetal and adult DP cells. Among them, Spondin-1, a Wnt agonist, was chosen for verification and can rescue hair follicle regeneration in skin reconstitution assays using cells from adult mice. Additionally, twenty-nine transcription factors were significantly upregulated in fetal DP compared to adult DP cells. Of those, seven transcription factor binding motifs were significantly enriched in the candidate promoter regions of differentially expressed genes between fetal and adult DP cells, suggesting a combinatorial regulatory role in the fetal DP phenotype. Further investigation into these regulators is warranted to determine if these proteins and/or associated pathways plays a role in the maintenance or modulation of DP cells to induce hair regeneration.

2020-11-16 | GSE149189 | GEO

Expression data of freshly microdissected human hair follicle dermal papilla and its comparisons

Project description:The dermal papilla (DP) of the hair follicle plays crucial roles in the hair follcie morphogenesis and cycling. Thus, the elucication of human DP molecular signature is of great interest. DP cell culture by conventional method impairs intrinsic properties of DP cells. Isolatoion of human DP is hampered by the lack of specific cell surface markers. Thus, it still depends on manual microdissection, with which the removal of minor contamination is unfeasible. Cultured DP cells are mostly pure. Aggregation of cultured DP cells was shown to restore some intrinsic properties in cultured DP cells. Fibroblasts are distinct dermal cell population and provide baseline for DP arrays.

2011-08-11 | GSE31324 | GEO

High-throughput sequencing of extracellular vesicles from human dermal papilla cells

Project description:The use of dermal papilla cells for hair follicle (HF) regeneration is long accepted much attention. However, cultured dermal papilla cells tend to lose the hair-inducible capability during passaging, which restricts its application. Increasing evidences indicate that dermal papilla cells exert their regulatory function of HF growth mainly through their unique paracrine properties, opening up a way to exosome therapies.This study aimed to explore the effects of exosomes from high and low-passaged human scalp follicle dermal papilla cells (DP-Exos) on hair follicle stem cells (HFSCs) activation and hair growth, and to investigate the underline mechanism. DP-Exos were isolated by ultracentrifugation and cultured with human scalp follicles and HFSCs. The hair elongation and cell proliferation was assessed. Quantitative real-time PCR (qRT-PCR) and Western-blot were performed to detect the expression levels of a class of miRNAs and proteins which have positive roles in regulating hair growth and HFSCs proliferation. High throughput miRNA sequencing of miRNAs in high (P8) and low-passaged (P3) DP-Exos was performed, and the utmost miRNA and its target gene was identified via bioinformatics analysis.

2021-01-13 | GSE136241 | GEO

Expression data from control siRNA and β-catenin siRNA transfected cultured mouse dermal cells

Project description:β-catenin activity of dermal cells is crucial for hair follicle neogenesis and strongly suggest that transcriptional target genes of β-catenin pathway are essential for maintaining trichogenicity of dermal cells. We used microarrays to identify genes targeted by the β-catenin pathway that are essential for maintaining the trichogenicity of dermal cells.

2013-09-03 | GSE50525 | GEO

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