Inhibition of beta-catenin signalling in dermal fibroblasts enhances hair follicle regeneration during wound healing
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE83117 | GEO | 2016/07/18
SECONDARY ACCESSION(S): PRJNA324815
REPOSITORIES: GEO
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Project description:We performed gene expression profiling of P1 and P5 back and tail dermis to uncover potential explanations for the differences in HF formation at different ages and in different body sites. To generate back and tail dermis microarray from P1 mouse (C57Bl6/CBA F1), tail skin was incubated in 5mM EDTA/PBS solution at 37°C, 1h, whereas back skin was incubated in dispase-trypsin solution at 37°C, 1h. Tail and back skin dermis were separated from the epidermis with forceps, washed once in PBS and digested as described above. Single-cell suspensions were washed 3x in PBS, before cells were lysed in Trizol (Invitrogen) and RNA was purified using Qiagen RNeasy columns. RNA was extracted from triplicate mice. cDNA was amplified from purified RNA and hybridized to Affymetrix MG430.2A arrays by the Cancer Research UK Patterson Institute Affymetrix Genechip Microarray Service. Array images were produced by the Affymetrix PICR 3000 scanner and analysed as Cell files using Genespring-13X (Agilent Technologies). RMA normalization was used and the bottom twentieth-percentile of genes (i.e., the 20% of genes with the lowest expression levels) were excluded from subsequent analysis.
2016-07-18 | E-GEOD-83117 | biostudies-arrayexpress
Project description:New hair follicles (HFs) do not form in adult mammalian skin unless epidermal Wnt signalling is activated genetically or within large wounds. To understand the postnatal loss of hair forming ability we monitored HF formation at small circular (2 mm) wound sites. At P2, new HFs formed in back skin, but HF formation was markedly decreased by P21. Neonatal tail also formed wound-associated HFs, albeit in smaller numbers. Postnatal loss of HF neogenesis did not correlate with wound closure rate but with a reduction in Lrig1-positive papillary fibroblasts in wounds. Comparative gene expression profiling of back and tail dermis at P1 and dorsal fibroblasts at P2 and P50 showed a correlation between loss of HF formation and decreased expression of genes associated with proliferation and Wnt/β-catenin activity. Between P2 and P50, fibroblast density declined throughout the dermis and clones of fibroblasts became more dispersed. This correlated with a decline in fibroblasts expressing a TOPGFP reporter of Wnt activation. Surprisingly, between P2 and P50 there was no difference in fibroblast proliferation at the wound site but Wnt signalling was highly upregulated in healing dermis of P21 compared with P2 mice. Postnatal β-catenin ablation in fibroblasts promoted HF regeneration in neonatal and adult mouse wounds, whereas β-catenin activation reduced HF regeneration in neonatal wounds. Our data support a model whereby postnatal loss of hair forming ability in wounds reflects elevated dermal Wnt/β-catenin activation in the wound bed, increasing the abundance of fibroblasts that are unable to induce HF formation.
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Project description:Tissue-engineered skin represents a useful strategy for the treatment of deep skin injuries and might contribute to the understanding of skin regeneration. The use of dermal papilla cells (DPCs) as a dermal component in a permanent composite skin with human hair follicle stem cells (HFSCs) was evaluated by studying the tissue-engineered skin architecture, stem cell persistence, hair regeneration, and graft-take in nude mice. A porcine acellular dermal matrix was seeded with HFSCs alone and with HFSCs plus human DPCs or dermal fibroblasts (DFs). In vitro, the presence of DPCs induced a more regular and multilayered stratified epidermis with more basal p63-positive cells and invaginations. The DPC-containing constructs more accurately mimicked the skin architecture by properly stratifying the differentiating HFSCs and developing a well-ordered epithelia that contributed to more closely recapitulate an artificial human skin. This acellular dermal matrix previously repopulated in vitro with HFSCs and DFs or DPCs as the dermal component was grafted in nude mice. The presence of DPCs in the composite substitute not only favored early neovascularization, good assimilation and remodeling after grafting but also contributed to the neovascular network maturation, which might reduce the inflammation process, resulting in a better healing process, with less scarring and wound contraction. Interestingly, only DPC-containing constructs showed embryonic hair bud-like structures with cells of human origin, presence of precursor epithelial cells, and expression of a hair differentiation marker. Although preliminary, these findings have demonstrated the importance of the presence of DPCs for proper skin repair.
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Project description:Dermal papilla cells isolated from the human hair follicle are capable of inducing hair growth in recipient epithelia. However, demonstrating disparity from rodent dermal papilla, human cells lose this inductive competance immediately upon growth in culture under normal growth conditions. We grew dermal papilla cells in hanging drop cultures that are morphologically akin to intact dermal papilla, and found that by enhancing the environment for aggregation, we could restore the inductive capacity of human dermal papilla cells in culture. The underlying genes that regulate the inductive potential of dermal papilla cells is not well understood, and we sought to use global profiling to identify key genes and pathways related to inductive competance within dermal papilla cells. We used Affymetrix microarrays to profile human dermal papilla cells in both hair inducing, and non-hair inducing states. Affymetrix microarrays were used to to perform profiling of human dermal papilla cells, both as intact tissues (freshly isolated from scalp), and at several stages in subsequent two dimensional culture; cell explant outgrowths (p0), cells at passage 1 (p1), passage 3 (p3) and passage 5 (p5). RNA was isolated from cultured cells 72 hours after feeding. Cells at passage 3 were also grown in hanging drops to form dermal spheroids, that were used for RNA collection 48 hours after establishment. All experiments were performed using tissue from three biological replicates (#D5, D6, D7),
2013-10-20 | E-GEOD-44765 | biostudies-arrayexpress
Project description:In our study, we found that skin depilation increased the number of DPCs and DSCs homing to HF niches. In order to screen out the chemokines upregulated after skin depilation, we carried out transcriptome analysis of mRNA expression profiles of depilated NOD/SCID skin sample at 0h, 1h, 4h, 12h, 1 days, 2 days, 4 days and 6 days after depilation.
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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/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. We prospectively isolated control and cÎex3 DS cells (YFP+ve CD34-ve ALP-ve ITGα8-ve cells) from P15 dorsal skins by FACS.
2016-05-31 | E-GEOD-81615 | biostudies-arrayexpress
Project description:Hair follicle stem cells in the epithelial bulge are responsible for the continual regeneration of the hair follicle during cycling. The bulge cells reside in a niche composed of dermal cells. The dermal compartment of the hair follicle consists of the dermal papilla and dermal sheath. Interactions between hair follicle epithelial and dermal cells are necessary for hair follicle morphogenesis during development and in hair reconstitution assays. Dermal papilla and dermal sheath cells express specific markers and possess distinctive morphology and behavior in culture. These cells can induce hair follicle differentiation in epithelial cells and are required in hair reconstitution assays either in the form of intact tissue, dissociated freshly prepared cells or cultured cells. This review will focus on hair follicle dermal cells since most therapeutic efforts to date have concentrated on this aspect of the hair follicle, with the idea that enriching hair-inductive dermal cell populations and expanding their number by culture while maintaining their properties, will establish an efficient hair reconstitution assay that could eventually have therapeutic implications.
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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/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.
2016-05-31 | GSE81615 | GEO
Project description:Mammalian wounds typically heal by fibrotic repair without hair follicle (HF) regeneration. Fibrosis and regeneration are currently considered the opposite end of wound healing. This study sought to determine if scar could be remodeled to promote healing with HF regeneration. Here, we identify that activation of the Sonic hedgehog (Shh) pathway reinstalls a regenerative dermal niche, called dermal papilla, which is required and sufficient for HF neogenesis (HFN). Epidermal Shh overexpression or constitutive Smoothened dermal activation results in extensive HFN in wounds that otherwise end in scarring. While long-term Wnt activation is associated with fibrosis, Shh signal activation in Wnt active cells promotes the dermal papilla fate in scarring wounds. These studies demonstrate that mechanisms of scarring and regeneration are not distant from one another and that wound repair can be redirected to promote regeneration following injury by modifying a key dermal signal.
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Project description:Global expression analysis of neural crest-like skin-derived precursors (SKPs) and Sox2-positive follicle dermal cells that SKPs originate from. In spite of the remarkable regenerative capacity of mammalian skin, an adult dermal stem cell has not yet been identified. Here, we provide evidence that SKPs, multipotent neural crest-like skin-derived precursors, represent an adult dermal stem cell. When transplanted into adult skin, SKPs can reconstitute the adult dermis, contribute to dermal wound-healing, home to a hair follicle niche, and instruct epidermal cells to make hair follicles. Hair follicle-derived SKPs self-renew, maintain their multipotency, and serially reconstitute hair follicles. The endogenous origin of SKPs are Sox2-positive follicle dermal cells that share a similar global gene expression profile with SKPs. These endogenous cells home back to their follicle niche, induce hair follicle morphogenesis, and differentiate into neural and dermal progeny. Hair follicle-associated dermal cells will move out of their niche to contribute to dermal maintenance and wound-healing. These studies therefore identify a dermal stem cell, and provide a biological rationale for the presence of a multipotent precursor within adult dermis, findings with important therapeutic implications.
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