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Innate immunity controls hair regeneration and growth via BMP signaling

ABSTRACT: Tight immune defense against environment and a unique ability of self-repair are the hallmarks of epithelia. Here we show that innate immunity Toll like receptor 2 (TLR2) coordinates these key functions thereby promoting hair growth and tissue regeneration. TLR2 is enriched in hair follicle stem cells (HFSCs) and its levels change in hair cycle and skin disorders. The lack of TLR2 in HFSCs diminishes activation and proliferation of HFSCs markedly prolonging the resting phase of hair cycle. Transcriptome profiling of HFSCs revealed that TLR2 regulates main hair regeneration pathways. TLR2 deletion upregulates inhibitory BMP7 signaling, while the blockade by Noggin restores deficient HFSCs proliferation in the absence of TLR2. In injury model TLR2 is required for both, tissue and hair regeneration. While endothelial TLR2 drives wound revascularization and closure, HFSC TLR2 controls hair regrowth. Endogenous TLR2 ligand produced in hair follicles promotes hair regeneration and growth via HFSC TLR2. Together, HFSC TLR2 drives stem cell proliferation, hair cycle and regeneration.

ORGANISM(S): Mus musculus

PROVIDER: GSE179300 | GEO | 2024/01/04

REPOSITORIES: GEO

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Corticosterone inhibits Gas6 to govern hair follicle stem cell quiescence

Project description:Chronic, sustained exposure to stressors can profoundly impact tissue homeostasis, although the mechanisms by which these changes occur are largely unknown. Here, we report the adrenal gland-derived stress hormone corticosterone (the rodent equivalent of cortisol) regulates hair follicle stem cell (HFSC) quiescence and hair growth in mice. Without systemic corticosterone, HFSCs enter substantially more rounds of the regeneration cycle throughout life. Conversely, under chronic stress, elevated corticosterone levels prolong HFSC quiescence and keep hair follicles in an extended resting phase. Mechanistically, corticosterone acts on dermal papilla (DP) to suppress the expression of a secreted factor, Growth Arrest Specific 6 (Gas6). Restoring Gas6 expression overcomes stress-induced inhibition of HFSC activation and hair growth. Our work identifies corticosterone as a systemic inhibitor of HFSC activity via its impact on the niche, and demonstrates that removal of such inhibition drives HFSCs into frequent regeneration cycles with no observable defects long-term.

2021-02-13 | GSE135705 | GEO

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

Nfatc1 Orchestrates Aging in Hair Follicle Stem Cells

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

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

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

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

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

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Priming mobilization of hair follicle stem cells triggers permanent loss of regeneration after alkylating chemotherapy

Project description:The maintenance of genetic integrity is critical for stem cells to ensure homeostasis and regeneration. Little is known about how adult stem cells respond to irreversible DNA damage, resulting in loss of regeneration in humans. Here, we establish a permanent regeneration loss model using cycling human hair follicles treated with alkylating agents: busulfan followed by cyclophosphamide. We unravel the underlying mechanisms by which hair follicle stem cells (HFSCs) lose their pool. Contrary to immediate destructive changes in rapidly proliferating hair matrix cells, quiescent HFSCs show unexpected massive proliferation after busulfan and then undergo large-scale apoptosis following cyclophosphamide. HFSC proliferation is activated through PI3K/Akt pathway, and depletion is driven by p53/p38-induced cell death. RNA-seq analysis shows that HFSCs experience mitotic catastrophe with G2/M checkpoint activation. Our findings indicate that priming mobilization causes stem cells to lose their resistance to DNA damage, resulting in permanent loss of regeneration after alkylating chemotherapy.

2019-07-09 | GSE130054 | GEO

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