Photobiomodulation therapy for hair regeneration: A synergetic activation of β-CATENIN in hair follicle stem cells by ROS and paracrine WNTs.
Ontology highlight
ABSTRACT:
SUBMITTER: Jin H
PROVIDER: S-EPMC8190671 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
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.
| S-EPMC4958333 | biostudies-literature
Project description:Rationale: β-catenin signaling controls multiple fibroblast subsets, with its overactivity promoting the differentiation of hair follicle dermal stem cells (hfDSCs) and the hyperactivation of interfollicular fibroblasts. Understanding the concept of hfDSC activation and modulation offers hope towards the therapeutic armamentarium in dermatology and related comorbidities, as well as their potential applications in gerontology (the study of physiological aging). Having a comprehensive understanding in this stochastic process could also further yield important, novel insights into the molecular basis of skin aging to improve lifespan and preventing aging-related diseases. Methods: A new CD34CrePGR mouse line was generated. Through fate-tracing models and a series of β-catenin genetic experiments, our study depicts how the wound environment increases phosphorylated β-catenin in hfDSCs and facilitates their differentiation into dermal papilla (DP) and dermal sheath (DS). In mice carrying hfDSC-specific activated allele of β-catenin, hfDSCs accelerated their differentiation into DP cells. Results: Notably, with β-catenin stabilization in CD34-expressing cells and potential activation of canonical Wnt signaling, the mutant mice showed a brief increase of hair density in the short term, but over time leads to a senescence phenotype developing premature canities and thinning [hair follicle (HF) miniaturization]. Conclusion: β-catenin signaling drove HF senescence by accelerating differentiation of CD34+ hfDSCs, resulting in phenotypes attributable to the differentiation of the hfDSCs into DP cells and the loss of their stem cell potential. Therefore, our study reveals that the regulation of β-catenin signaling in hfDSCs may potentially become an important subject for future exploration in development of clinically effective therapies for hair loss treatment and an excellent model for revealing new therapeutic approaches to reverse aging or retarding the development of alopecia.
| S-EPMC9037041 | biostudies-literature
Project description:Skin stem cells can regenerate epidermal appendages; however, hair follicles (HF) lost as a result of injury are barely regenerated. Here we show that macrophages in wounds activate HF stem cells, leading to telogen-anagen transition (TAT) around the wound and de novo HF regeneration, mostly through TNF signalling. Both TNF knockout and overexpression attenuate HF neogenesis in wounds, suggesting dose-dependent induction of HF neogenesis by TNF, which is consistent with TNF-induced AKT signalling in epidermal stem cells in vitro. TNF-induced β-catenin accumulation is dependent on AKT but not Wnt signalling. Inhibition of PI3K/AKT blocks depilation-induced HF TAT. Notably, Pten loss in Lgr5+ HF stem cells results in HF TAT independent of injury and promotes HF neogenesis after wounding. Thus, our results suggest that macrophage-TNF-induced AKT/β-catenin signalling in Lgr5+ HF stem cells has a crucial role in promoting HF cycling and neogenesis after wounding.
| S-EPMC5378973 | biostudies-literature
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:The activation of tissue stem cells from their quiescent state represents the initial step in the complex process of organ regeneration and tissue repair. While the identity and location of tissue stem cells are becoming known, how key regulators control the balance of activation and quiescence remains mysterious. The vertebrate hair is an ideal model system where hair cycling between growth and resting phases is precisely regulated by morphogen signaling pathways, but how these events are coordinated to promote orderly signaling in a spatial and temporal manner remains unclear. Here, we show that hair cycle timing depends on regulated stability of signaling substrates by the ubiquitin-proteasome system. Topical application of partial proteasomal inhibitors (PaPIs) inhibits epidermal and dermal proteasome activity throughout the hair cycle. PaPIs prevent the destruction of the key anagen signal β-catenin, resulting in more rapid hair growth and dramatically shortened telogen. We show that PaPIs induce excess β-catenin, act similarly to the GSK3β antagonist LiCl, and antagonize Dickopf-related protein-mediated inhibition of anagen. PaPIs thus represent a novel class of hair growth agents that act through transiently modifying the balance of stem cell activation and quiescence pathways.
| S-EPMC4116182 | biostudies-literature
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. Here, we uncover a hitherto unrecognized DP transmitter, TGF-β2, which activates Smad2/3 transiently in HFSCs concomitant with entry into tissue regeneration. This signaling is critical: HFSCs that cannot sense TGF-β exhibit significant delays in HF regeneration, whereas exogenous TGF-β2 stimulates HFSCs in vivo and in vitro. By engineering TGF-β- and BMP-reporter mice, we show that TGF-β2 signaling antagonizes BMP signaling in HFSCs but not through competition for limiting Smad4-coactivator. Rather, our microarray, molecular, and genetic studies unveil Tmeff1 as a direct TGF-β2/Smad2/3 target gene, expressed by activated HFSCs and physiologically relevant in restricting and lowering BMP thresholds in the niche. Connecting BMP activity to an SC's response to TGF-βs may explain why these signaling factors wield such diverse cellular effects.
| S-EPMC3349223 | biostudies-literature
Project description:beta-Catenin signaling is required for hair follicle development, but it is unknown whether its activation is sufficient to globally program embryonic epidermis to hair follicle fate. To address this, we mutated endogenous epithelial beta-catenin to a dominant-active form in vivo. Hair follicle placodes were expanded and induced prematurely in activated beta-catenin mutant embryos, but failed to invaginate or form multilayered structures. Eventually, the entire epidermis adopted hair follicle fate, broadly expressing hair shaft keratins in place of epidermal stratification proteins. Mutant embryonic skin was precociously innervated, and displayed prenatal pigmentation, a phenomenon never observed in wild-type controls. Thus, beta-catenin signaling programs the epidermis towards placode and hair shaft fate at the expense of epidermal differentiation, and activates signals directing pigmentation and innervation. In transcript profiling experiments, we identified elevated expression of Sp5, a direct beta-catenin target and transcriptional repressor. We show that Sp5 normally localizes to hair follicle placodes and can suppress epidermal differentiation gene expression. We identified the pigmentation regulators Foxn1, Adamts20 and Kitl, and the neural guidance genes Sema4c, Sema3c, Unc5b and Unc5c, as potential mediators of the effects of beta-catenin signaling on pigmentation and innervation. Our data provide evidence for a new paradigm in which, in addition to promoting hair follicle placode and hair shaft fate, beta-catenin signaling actively suppresses epidermal differentiation and directs pigmentation and nerve fiber growth. Controlled downregulation of beta-catenin signaling is required for normal placode patterning within embryonic ectoderm, hair follicle downgrowth, and adoption of the full range of follicular fates.
| S-EPMC2516408 | biostudies-literature
Project description:Background and purposeThe promotion of hair regeneration and growth heavily depends on the activation of Wnt/β-catenin signalling in the hair follicle, including dermal papilla (DP). KY19382, one of the newly synthesized analogues of indirubin-3'-monoxime (I3O), was identified as a Wnt/β-catenin signalling activator via inhibition of the interaction between CXXC-type zinc finger protein 5 (CXXC5) and dishevelled (Dvl). Given the close relationship between the Wnt/β-catenin signalling and hair regeneration, we investigated the effect of KY19382 on hair regrowth and hair follicle neogenesis.Experimental approachIn vitro hair induction effects of KY19382 were performed in human DP cells. The hair elongation effects of KY19382 were confirmed through the human hair follicle and vibrissa culture system. In vivo hair regeneration abilities of KY19382 were identified in three models: hair regrowth, wound-induced hair follicle neogenesis (WIHN) and hair patch assays using C57BL/6 mice. The hair regeneration abilities were analysed by immunoblotting, alkaline phosphatase (ALP) and immunohistochemical staining.Key resultsKY19382 activated Wnt/β-catenin signalling and elevated expression of ALP and the proliferation marker PCNA in DP cells. KY19382 also increased hair length in ex vivo-cultured mouse vibrissa and human hair follicles and induced hair regrowth in mice. Moreover, KY19382 significantly promoted the generation of de novo hair follicles as shown by WIHN and hair patch assays.Conclusion and implicationsThese results indicate that KY19382 is a potential therapeutic drug that exhibits effective hair regeneration ability via activation of the Wnt/β-catenin signalling for alopecia treatments.
| S-EPMC8251890 | biostudies-literature
Project description:The mammalian hair follicle undergoes repeated bouts of regeneration orchestrated by a variety of hair follicle stem cells. The last decade has witnessed the emergence of the immune niche as a key regulator of stem cell behavior and hair follicle regeneration. Hair follicles chemotactically attract macrophages and T cells so that they are in range to regulate epithelial stem cell quiescence, proliferation and differentiation during physiologic and injured states. Disruption of this dynamic relationship leads to clinically significant forms of hair loss including scarring and non-scarring alopecias. In this review, we summarize key concepts behind immune-mediated hair regeneration, highlight gaps in the literature and discuss the therapeutic potential of exploiting this relationship for treating various immune-mediated alopecias.
| S-EPMC7214459 | biostudies-literature
Project description:Broad dermal Wnt signaling is required for patterned induction of hair follicle placodes and subsequent Wnt signaling in placode stem cells is essential for induction of dermal condensates, cell clusters of precursors for the hair follicle dermal papilla (DP). Progression of hair follicle formation then requires coordinated signal exchange between dermal condensates and placode stem cells. However, it remains unknown whether continued Wnt signaling in DP precursor cells plays a role in this process, largely due to the long-standing inability to specifically target dermal condensates for gene ablation. Here we use the Tbx18(Cre) knockin mouse line to ablate the Wnt-responsive transcription factor β-catenin specifically in these cells at E14.5 during the first wave of guard hair follicle formation. In the absence of β-catenin, canonical Wnt signaling is effectively abolished in these cells. Sox2(+) dermal condensates initiate normally; however by E16.5 guard hair follicle numbers are strongly reduced and by E18.5 most whiskers and guard hair follicles are absent, suggesting that active Wnt signaling in dermal condensates is important for hair follicle formation to proceed after induction. To explore the molecular mechanisms by which Wnt signaling in dermal condensates regulates hair follicle formation, we analyze genome-wide the gene expression changes in embryonic β-catenin null DP precursor cells. We find altered expression of several signaling pathway genes, including Fgfs and Activin, both previously implicated in hair follicle formation. In summary, these data reveal a functional role of Wnt signaling in DP precursors for embryonic hair follicle formation and identify Fgf and Activin signaling as potential effectors of Wnt signaling-regulated events.
| S-EPMC3933391 | biostudies-literature