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Regulatory T cells in skin promote hair follicle stem cell activation and hair growth through glucocorticoid signaling (ChIP-Seq)

ABSTRACT: The maintenance of tissue homeostasis in steady state or under stress is dependent on the proper communication between tissue-resident stem cells (SCs) and immune cells in their microenvironment or “niche”. In addition to promoting immune tolerance, regulatory T cells (Tregs) have recently emerged as a critical component of stem cell niche in the hair follicle (HF), injured muscle, bone marrow and intestine to support stem cell differentiation. How Treg cells sense the dynamic signals in the niche environment and communicate with stem cells during tissue regeneration is largely unknown. Here, by using HF as a model, we uncover a hitherto unrecognized function of glucocorticoid receptor (GR) signaling pathway in skin-resident Treg cells to facilitate hair follicle stem cell (HFSC) activation and HF regeneration. Ablation of GR signaling in Tregs blocked HFSCs activation and proliferation after hair depilation and during the natural hair growth cycle. Mechanistically, GR signaling induces skin-resident Tregs to produce TGF-b3, which activates Smad2/3 in HFSCs and promotes HFSC proliferation and hair growth. Our study identifies a novel crosstalk between skin-resident Tregs and HFSCs mediated by the GR/TGF-b3 axis, highlighting a new avenue to manipulate Tregs to support tissue regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE183804 | GEO | 2022/05/02

REPOSITORIES: GEO

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Regulatory T cells in skin promote hair follicle stem cell activation and hair growth through glucocorticoid signaling (RNA-Seq)

Project description:The maintenance of tissue homeostasis in steady state or under stress is dependent on the proper communication between tissue-resident stem cells (SCs) and immune cells in their microenvironment or “niche”. In addition to promoting immune tolerance, regulatory T cells (Tregs) have recently emerged as a critical component of stem cell niche in the hair follicle (HF), injured muscle, bone marrow and intestine to support stem cell differentiation. How Treg cells sense the dynamic signals in the niche environment and communicate with stem cells during tissue regeneration is largely unknown. Here, by using HF as a model, we uncover a hitherto unrecognized function of glucocorticoid receptor (GR) signaling pathway in skin-resident Treg cells to facilitate hair follicle stem cell (HFSC) activation and HF regeneration. Ablation of GR signaling in Tregs blocked HFSCs activation and proliferation after hair depilation and during the natural hair growth cycle. Mechanistically, GR signaling induces skin-resident Tregs to produce TGF-b3, which activates Smad2/3 in HFSCs and promotes HFSC proliferation and hair growth. Our study identifies a novel crosstalk between skin-resident Tregs and HFSCs mediated by the GR/TGF-b3 axis, highlighting a new avenue to manipulate Tregs to support tissue regeneration.

2022-05-02 | GSE183805 | 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

Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters

Project description:Tissue homeostasis and regeneration require activation and subsequent lineage commitment of tissue-resident stem cells (SCs). These state changes are controlled by epigenetic barriers. Using hair follicle stem cells (HFSCs) as paradigm, we studied how aging impacts the chromatin landscape and function of mammalian SCs. Analyses of genome-wide chromatin accessibility revealed that aged HFSCs displayed widespread reduction of chromatin accessibility specifically at key SC self-renewal and differentiation genes that were characterized by bivalent promoters carrying both activating and repressive chromatin marks. Consistently, aged HFSCs showed reduced self-renewing capacity and attenuated ability to activate expression of these bivalent genes upon regeneration. These functional defects were niche-dependent as transplantation of aged HFSCs into young recipients or into ex vivo niches restored SC functions and transcription of poised genes. Mechanistically, aged HFSC niche displayed wide-spread alterations in extracellular matrix composition and mechanics, resulting in compressive forces on SCs and subsequent transcriptional repression, leading to loss of bivalent promoters. Tuning tissue mechanics both in vivo and in vitro recapitulated age-related SC changes, implicating niche mechanics as a central regulator of genome organization and function leading to age-dependent SC exhaustion.

2021-05-07 | PXD018352 | Pride

In vivo transcriptional goverance of hair follicle stem cells by canonical Wnt regulators

Project description:Mouse hair follicles undergo synchronized cycles. Cyclical regeneration and hair growth is fueled by hair follicle stem cells (HFSCs). HFSCs regenerate hair in response to canonical Wnt signalling. We used RNA-seq to unfold genome-wide chromatin landscapes of β-catenin within the native HFSC-niche.

2013-12-03 | GSE48878 | GEO

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

2012-01-04 | GSE33471 | GEO

Transcriptional profiling of hair follicle stem cells in the presence and absence of Regulatory T-cells

Project description:Purpose: The goals of this study were to identify Pathways that Tregs utilize in the skin to maintain tissue homesostasis in the context of hair follcile cycling. Methods: Hair follicle stem cells (HFSCs), in the presence and absence of Tregs, were induced into cycle through a model of depilation induced anagen. HFSCs were then purified by cell sorting at day 4 post depilation based on cell surface marker expression (CD45 negative, MHC Class II negative, Sca-1 negative, EpCAM negative, CD34 Positive, Integrin alpha6 High) to generate mRNA transcription profiles. Results: Transcriptional profiling revealed a significant reduction in proliferation/differentiation associated genes expressed in HFSCs isolated from Treg depleted mice Conclusion: Our study represents the first detailed analysis of Treg modulation of tissue stem cell behaviour mRNA profiles of HFSC isolated from 7-10 week old WT and Foxp3-DTR mice at 4 days post depilation of dorsal skin.

2017-04-28 | E-GEOD-76102 | biostudies-arrayexpress

Sympathetic nerves and arrector pili muscles form a dual component niche to regulate hair follicle stem cells

Project description:Piloerection (goosebump) requires concerted actions of the hair follicle, the arrector pili muscle (APM), and the sympathetic nerve, providing a model to study interactions across epithelium, mesenchyme, and nerves. Here, we show that APMs and sympathetic nerves form a dual component niche to modulate hair follicle stem cell (HFSC) activity. Sympathetic nerves form synapse-like structures with HFSCs and regulate HFSCs through norepinephrine, whereas APMs maintain sympathetic innervation to HFSCs. Without norepinephrine signaling, HFSCs enter a deep quiescence state by down-regulating cell cycle machinery and mitochondria metabolism, while up-regulating quiescence regulators Lhx2, Foxp1, and Fgf18. During development, HFSC progeny secrets Sonic Hedgehog (SHH) to direct the formation of this APM-sympathetic nerve niche, which in turn controls hair follicle regeneration in adults. Our results reveal a reciprocal interdependence between a regenerative tissue and its niche at different stages, and illustrate that nerves can modulate stem cell quiescence through synapses and neurotransmitters.

2020-07-15 | GSE130240 | GEO

Nfatc1 Orchestrates Aging in Hair Follicle Stem Cells

Project description:Mouse hair follicles undergo synchronized cycles. Cyclical regeneration and hair growth is fueled by hair follicle stem cells (HFSCs). We used ChIP-seq to unfold genome-wide chromatin landscapes of Nfatc1 and dissect the biological relevence of its upstream BMP signaling in HFSC aging. Telogen quiescent hair follicle stem cells (HFSCs) were FACS-purified for ChIP-sequcencing.

2013-11-14 | E-GEOD-52328 | biostudies-arrayexpress

Stem cell quiescence acts as a tumor suppressor mechanism in hair follicle initiated squamous tumors

Project description:In many organs, adult stem cells are uniquely poised to serve as cancer cells of origin. In the epidermis, hair follicle stem cells (HFSCs) cycle through stages of quiescence (telogen) and proliferation (anagen) to drive hair growth. Within the hair follicle, HFSCs are capable of initiating squamous cell carcinoma, yet it is unclear how the hair cycle contributes to tumorigenesis. The data presented here show that HFSCs are unable to initiate tumors during the quiescent phase of the hair cycle, indicating that the mechanisms that keep HFSCs dormant are dominant to gain of oncogenes (Ras) or loss of tumor suppressors (p53). Instead, prolonged oncogenic stimuli only exert their effects when HFSC quiescence mechanisms are removed by normal HFSC activation. Furthermore, Pten activity is necessary for quiescence based tumor suppression, since Pten deletion alleviates this stem cell specific ability without affecting proliferation per se. Small RNAs were cloned from Trizol-lysed cells sorted from mouse skin and sequenced with the Illumina HiSeq2000.

2013-10-28 | E-GEOD-51765 | biostudies-arrayexpress

Functional stem cell aging dictated by skin tissue microenvironment

Project description:Organismal aging in mammals is manifested with architectural alteration and functional decline of multiple organs throughout the body. In aged skin, hairs are sparse, which has led to the hypothesis that the hair follicle stem cells (HFSCs) undergo epidermal differentiation during aging. Here, we employ single cell analysis to interrogate aging-related changes in the HFSCs. Unexpectedly, HFSCs maintain their lineage fidelity and show no signs of shifting to an epidermal fate. Despite maintaining lineage identity, HFSCs do show prevalent transcriptional changes in extracellular matrix genes. Of importance, these HFSC changes are accompanied by profound architectural perturbations in the aging stem cell niche. Upon surveying the dermis from young and aged skin, we also observe age-related changes in many non-epithelial cell types, including resident immune cells, sensory neurons, arrector pili muscles, and blood vessels – all of which have been previously associated with abilities to modulate hair follicle regeneration. Consistent with both intrinsic and extrinsic alterations in stem cell: niche communications, we find that in response to skin wounding, aged HFSCs repair the epidermis, but are defective in hair follicle regeneration. Intriguingly, whereas aged dermis cannot support young HFSCs, aged HFSCs can be rescued when supported by young dermis. Together, these findings favor a model where skin tissue microenvironment plays a dominant role in dictating the molecular properties and activities of HFSCs.

2019-12-31 | GSE124901 | GEO

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