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Epithelial-Mesenchymal Micro-Niches Govern Stem Cell Lineage Choices (ATAC-seq)

ABSTRACT: Adult tissue stem cells (SCs) reside in niches, which through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single cell RNA-sequencing, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage-tracing, temporal single cell analyses and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged uni-lineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: Some progenitors specify lineages immediately; others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.

ORGANISM(S): Mus musculus

PROVIDER: GSE96782 | GEO | 2017/04/18

SECONDARY ACCESSION(S): PRJNA379620

REPOSITORIES: GEO

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Epithelial-Mesenchymal Micro-Niches Govern Stem Cell Lineage Choices (SC RNA-Seq)

Project description:Adult tissue stem cells (SCs) reside in niches, which through intercellular contacts and signaling, influence SC behavior. Once activated, SCs typically give rise to short-lived transit-amplifying cells (TACs), which then progress to differentiate into their lineages. Here, using single cell RNA-sequencing, we unearth unexpected heterogeneity among SCs and TACs of hair follicles. We trace the roots of this heterogeneity to micro-niches along epithelial-mesenchymal interfaces, where progenitors display molecular signatures reflective of spatially distinct local signals and intercellular interactions. Using lineage-tracing, temporal single cell analyses and chromatin landscaping, we show that SC plasticity becomes restricted in a sequentially and spatially choreographed program, culminating in seven spatially arranged uni-lineage progenitors within TACs of mature follicles. By compartmentalizing SCs into micro-niches, tissues gain precise control over morphogenesis and regeneration: Some progenitors specify lineages immediately; others retain potency, preserving self-renewing features established early while progressively restricting lineages as they experience dynamic changes in microenvironment.

2017-04-18 | GSE90848 | GEO

Epithelial-Mesenchymal Micro-Niches Govern Stem Cell Lineage Choices (bulk RNA-Seq)

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Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage

Project description:Mouse hair follicles (HFs) undergo synchronized cycles. Cyclical regeneration and hair growth is fueled by stem cells (SCs). During the rest phase, the HF-SCs remain quiescent due to extrinsic inhibitory signals within the niche. As activating cues accumulate, HF-SCs become activated, proliferate, and grow downward to form transient-amplifying matrix progenitor cells. We used microarrays to detect the relative levels of global gene expression underlying the states of hair follicle stem cells and their transient-amplifying progeny before differentiation. Quiescent hair follicle stem cells (qHF-SCs), activated hair follicle stem cells (aHF-SCs) and transient-amplifying matrix cells (HF-TACs) were FACS-purified for RNA extraction and hybridization on Affymetrix microarrays. To obtain homogeneous populations of expression profiles, we applied the FACS technique to purify SC and TACs according to their cell surface markers.

2011-09-01 | E-GEOD-31028 | biostudies-arrayexpress

Genome-wide maps of histone modifications unwind in vivo chromatin states of the hair follicle lineage [ChIP-Seq]

Project description:Mouse hair follicles undergo synchronized cycles. Cyclical regeneration and hair growth is fueled by stem cells (SCs). During the rest phase, the HF-SCs remain quiescent due to extrinsic inhibitory signals within the niche. As activating cues accumulate, HF-SCs become activated, proliferate, and grows downward to form transient-amplifying matrix progenitor cells. We used ChIP-seq to reveal the genome-wide maps of histone modifications underlying the states of hair follicle stem cells and their transient-amplifying progeny before differentiation. Quiescent hair follicle stem cells (qHF-SCs), activated hair follicle stem cells (aHF-SCs) and transient-amplifying matrix cells (HF-TACs) were FACS-purified for ChIP-sequcencing.

2011-09-02 | E-GEOD-31239 | biostudies-arrayexpress

Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression [ATAC-seq]

Project description:Tissue regeneration relies on resident stem cells (SCs), whose activity and lineage choices are influenced by microenvironment. Exploiting the synchronized, cyclical bouts of tissue regeneration in hair follicles (HFs), we investigate how microenvironment dynamics shape the emergence of SC lineages. Employing epigenetic and ChIP-seq profiling, we uncover how signal-dependent transcription factors couple spatio-temporal cues to chromatin dynamics, thereby choreographing SC lineages. Using enhancer-driven reporters, mutagenesis and genetics, we show that simultaneous BMP-inhibitory and WNT signals set the stage for lineage choices by establishing chromatin platforms permissive for diversification. Mechanistically, when binding of BMP-effector pSMAD1 is relieved, super-enhancers driving HF-SC master regulators become silenced. Concomitantly, multipotent, lineage-fated super-enhancers silent in HF-SCs become activated by exchanging WNT-effectors TCF3/4 for LEF1. Throughout regeneration, lineage super-enhancers continue reliance upon LEF1, but then achieve specificity by accommodating additional incoming signaling effectors. Barriers to progenitor plasticity mount as diverse, signal-sensitive transcription factors shape LEF1-regulated super-enhancer dynamics.

2018-01-11 | GSE100875 | GEO

Temporal Layering of Signaling Effectors Drives Chromatin Remodeling during Hair Follicle Stem Cell Lineage Progression [RNA-seq]

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An RNAi screen unveils a new player in stem cell self-renewal and long-term regeneration

Project description:Mouse hair follicles undergo synchronized cycles. Cyclical regeneration and hair growth is fueled by stem cells (SCs). Following hair regeneration, SCs within the bulge and its vicinity (upper ORS which becomes the bulge for the next cycle) briefly self-renew to replenish expended SCs and ensure long-term tissue regeneration. We used microarrays to detect the relative levels of global gene expression influenced by transcription factor Tbx1 in order to gain insight into how Tbx1 is invovled in regulating hair follicle SC self-renewal and long-term regeneration. Fourty eight hours after deplicaiton induced hair regeneration, hair follicle SCs were FACS-purified for RNA extraction and hybridization on Affymetrix microarrays. To obtain homogeneous populations of expression profiles, we applied FASC technique to purify SC according to their cell surface markers.

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Signaling networks of developing hair follicles

Project description:The hair follicle (HF) is a complex miniorgan that serves as an ideal model system to study stem cell (SC) interactions with the niche during growth and regeneration. Dermal papilla (DP) cells are required for activating SCs during the adult hair cycle, but the signal exchange between niche and SC precursors/transit amplifying progenitor cells (TACs) that regulates HF morphogenetic growth is largely unknown. Here we use six transgenic reporters to isolate 14 major skin and HF cell populations. With next-generation RNA sequencing we characterize their transcriptomes and define unique molecular signatures. SC precursors, TACs and the DP niche express a plethora of known and novel ligands and receptors. Signaling interaction network analysis reveals a birds-eye view of pathways implicated in epithelial-mesenchymal interactions. Using a systematic tissue-wide approach this work provides a comprehensive platform, linked to an interactive online database, to identify and further explore the SC/TAC/niche crosstalk regulating HF growth.

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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

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