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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE51765 | GEO | 2013/10/28

SECONDARY ACCESSION(S): PRJNA224969

REPOSITORIES: GEO

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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

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

Hair growth is induced by blockade of macrophage-derived oncostatin M and JAK-STAT5 signaling in hair follicle stem cells.

Project description:We also show that OSM is sufficient for maintaining quiescence of hair follicle stem cells (HFSCs), and OSMRβ-JAK-STAT5 signaling is necessary for maintaining the resting phase of the hair cycle (telogen). Using single-cell RNA sequencing, we identify the source of OSM to be a distinct subset of TREM2+ macrophages that predominate during early telogen. Moreover, inhibition of macrophages during telogen by genetic ablation, neutralizing antibodies and small-molecule inhibitors was sufficient to induce anagen.

2019-04-09 | GSE108709 | 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

Foxc1 reinforces quiescence in hair follicle stem cells

Project description:Quiescent stem cells are periodically activated to maintain tissue homeostasis or occasionally called into action upon injury. Molecular mechanisms that constitutively maintain stem cell identity or promote stem cell proliferation and differentiation upon activation have been extensively studied. However, it is unclear how quiescent stem cells maintain identity and reinforce quiescence when they transition from quiescence to activation. Here we show mouse hair follicle stem cell compartment induces a transcription factor, Foxc1, when activated. Importantly, deletion of Foxc1 in the activated but not quiescent stem cells compromises stem cell identity, fails to re-establish quiescence and subsequently drives premature stem cell activation.These findings uncover a dynamic, cell-intrinsic mechanism employed by hair follicle stem cells to reinforce stemness in response to activation. Poly(A)-enriched transcriptome RNA-seq on HFSCs isolated in WT and K14Cre cKO mice at anagen and early telogen stage of hair cycle.

2016-02-05 | E-GEOD-67404 | biostudies-arrayexpress

Gene expression profile of hair follicle stem cells (HFSCs) isolated from wild type and homozygous Dab2 cKO (Dab2 Fl/Fl) mice at postnatal day 35

Project description:Disabled 2 is an endocytic adaptor protein known to regulate various signaling pathways such Wnt , BMP, TGF and Ras/MAPK. In the present study, we observed that Dab2 is expressed in all the compartments of the hair follicle. K14 Cre specific homozygous Dab2 knockout resulted in delayed activation of HFSCs and delayed Ist hair follicle cycle initiation. At PD35, while WT progresses to anagen II, the Dab2 cKO mice still remains at telogen. In addition, loss of Dab2 alos led to reduced HFSCs pool extended quiescence, and reduced self renewal capacity of HFSCs at PD35. We performed expression profiling of HFSCs isolated from WT and Dab2 cKO mice at PD35 to check for the differentially regulated genes involved in HFSCs activation. The expression analysis helped us to elucidate the detailed molecular mechanisms involved in Dab2 mediated regulation of HFSCs activation and quiescence.

2024-03-01 | GSE250300 | GEO

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

FGF18 Signaling for Hair Cycle Resting Phase Determines Radioresistance of Hair Follicles by the Arrest of Hair Cycling

Project description:Telogen (resting phase) hair follicles are more radioresistant than anagen (growth phase) ones. Irradiation of BALB/c mice in the anagen phase with γ-rays at 6 Gy induced hair follicle dystrophy, whereas irradiation in the telogen phase induced the arrest of hair follicle elongation without any dystrophy after post-irradiation depilation. In contrast, FGF18 was highly expressed in the telogen hair follicles to maintain the telogen phase and also the quiescence of hair follicle stem cells. Therefore, the inhibition of FGF receptor signaling at telogen induced the dystrophy after post-irradiation depilation. In addition, the administration of recombinant FGF18 suppressed cell proliferation in the hair follicles and enhanced the repair of radiation-induced DNA damage, so FGF18 protected the anagen hair follicles against radiation damage to enhance hair regeneration. Moreover, FGF18 reduced the expression of cyclin B1 and cdc2 in the skin and FGF18 signaling induced G2/M arrest in the keratinocyte cell line HaCaT, although no obvious change of the expression of DNA repair genes was detected by DNA microarray analysis. These findings suggest that FGF18 signaling for the hair cycle resting phase causes radioresistance in telogen hair follicles by arresting the proliferation of hair follicle cells.

2017-06-03 | GSE69501 | GEO

Signaling couples hair follicle stem cell quiescence with reduced histone H3K4/K9/K27me3 for proper tissue homeostasis

Project description:Mechanisms of plasticity to acquire different cell fates are critical for adult stem cell (SC) potential, yet are poorly understood. Reduced global histone methylation is an epigenetic state known to mediate plasticity in cultured embryonic SCs and T cell progenitors. We used mouse hair follicle stem cells (HFSCs) at two different hair cycle stages (early anagen and late catagen) to compare the genome-wide changes in the levels of histone modification marks H3K4me3, H3K9me3, and H3K27me3. Hair follicle stem cells from Early Anagen (EA-HFSCs) and Late Catagen (LC-HFSCs), and their non-HFSCs counterparts (nEA-HFSCs and nLC-HFSCs), were FACS-isolated for Chromatin Immunoprecipitation followed by sequencing (ChIP-seq) analysis of H3K4me3, H3K9me3, and H3K27me3.

2016-04-13 | E-GEOD-78749 | biostudies-arrayexpress

RNA-seq analysis of hair follicle stem cell transcriptome upon loss of the transcription factor FOXC1

Project description:We report downstream gene expression changes in stem cells of the adult mouse hair follicle upon conditional ablating of the transcription factor Forkhead Box C1 transcription factor (FOXC1). Hair follicles undergo cycles of rest (telogen; Tel) and regeneration (anagen; Ana). As such, we performed our analysis on these two different stages of hair follicles. mRNA-sequencing of WT vs. Foxc1-conditional or inducible KO (Foxc1-cKO or iKO) hair follicle stem cells (HFSCs) purified from mouse dorsal back skin by flow-activated cell sorting (FACS).

2016-02-16 | E-GEOD-77256 | biostudies-arrayexpress

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