Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE148619 | GEO | 2021/05/06
REPOSITORIES: GEO
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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
Project description:Niche stiffening compromises stem cell potential during aging by reducing chromatin accessibility at bivalent promoters
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Project description:Mouse back skin was disassociated to single cells, sorted by cell surface markers and tested by microarrray To compare the gene expression of mouse bulge (CD34+CD200+CD49+) versus secondary hair germ (CD34-CD200+CD49+) versus interfollicular epidermis (CD34-CD200-CD49+) xx Bald scalp retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells Androgenetic alopecia (AGA) or common baldness results from a marked decrease in hair follicle size. This miniaturization may be related to loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from the same individuals for the presence of hair follicle stem and progenitor cells using flow cytometry to quantitate cells expressing CYTOKERATIN 15 (KRT15), CD200, CD34 and ALPHA-6-INTEGRIN (ITGA6). High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. Cells with the highest level of KRT15 expression were maintained in bald scalp; however, distinct populations of CD200high ITGA6high cells and CD34-positive cells were markedly diminished. Consistent with a progenitor cell phenotype, the diminished populations localized closely to the stem-cell rich bulge area but were larger and more proliferative than the bulge stem cells. In functional assays, analogous CD200 high /Itga6 high cells from murine hair follicles were multipotent and generated new hair follicles in skin reconstitution assays. These findings suggest that a defect in stem cell activation plays a role in the pathogenesis of AGA. 4 independent biologic replicates (each pooled from 3 distinct mice) were sorted for Mouse bulge (CD34+CD200+CD49+) versus secondary hair germ (CD34-CD200+CD49+) versus interfollicular epidermis (CD34-CD200-CD49+)
2011-01-12 | E-GEOD-21568 | biostudies-arrayexpress
Project description:A permantly active form of the oncogene Akt was expressed in the keratinocytes of the basal proliferative layer of the epidermis. Stem cells of the hair follicle expressing the cell surface marker CD34 were isolated. RNA form the CD34(+) and CD34(-) keratinocytes was extracted and and hybridized to Mouse Genome 430 2.0 Affymetrix arrays. Gene expression was compared between CD34(+) hair follicle stem cells and CD34(-) cells isolates from the back skin of K5-myrAkt transgenic mice.
2014-01-26 | E-GEOD-48522 | biostudies-arrayexpress
Project description:Mouse hair follicles undergo synchronized cycles. Cyclical regeneration and hair growth is fueled by hair follicle stem cells (HFSCs). We used RNA-seq to identify SOX9-dependent transcriptional changes and ChIP-seq to identify SOX9-bound genes in HF-SCs. Telogen quiescent hair follicle stem cells (HFSCs) and intefollicular epidermal cells (IFE) were FACS-purified for ChIP-sequcencing and HFSCs for RNA-Sequencing
2014-01-28 | E-GEOD-54424 | biostudies-arrayexpress
Project description:Mouse back skin was disassociated to single cells, sorted by cell surface markers and tested by microarrray To compare the gene expression of mouse bulge (CD34+CD200+CD49+) versus secondary hair germ (CD34-CD200+CD49+) versus interfollicular epidermis (CD34-CD200-CD49+) xx Bald scalp retains hair follicle stem cells but lacks CD200-rich and CD34-positive hair follicle progenitor cells Androgenetic alopecia (AGA) or common baldness results from a marked decrease in hair follicle size. This miniaturization may be related to loss of hair follicle stem or progenitor cells. To test this hypothesis, we analyzed bald and non-bald scalp from the same individuals for the presence of hair follicle stem and progenitor cells using flow cytometry to quantitate cells expressing CYTOKERATIN 15 (KRT15), CD200, CD34 and ALPHA-6-INTEGRIN (ITGA6). High levels of KRT15 expression correlated with stem cell properties of small cell size and quiescence. Cells with the highest level of KRT15 expression were maintained in bald scalp; however, distinct populations of CD200high ITGA6high cells and CD34-positive cells were markedly diminished. Consistent with a progenitor cell phenotype, the diminished populations localized closely to the stem-cell rich bulge area but were larger and more proliferative than the bulge stem cells. In functional assays, analogous CD200 high /Itga6 high cells from murine hair follicles were multipotent and generated new hair follicles in skin reconstitution assays. These findings suggest that a defect in stem cell activation plays a role in the pathogenesis of AGA.
2011-01-12 | GSE21568 | GEO
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
Project description:Epidermal keratinocytes were isolated from adult murine skin and FACS sorted into three populations based on their surface maker expression of alpha 6 integrin, CD34 and Sca-1. <br>- Alpha 6 positive cells constitute the entire population of basal or proliferative keratinocytes from the interfollicular epidermis and hair follicle. Both BIB and Bulge cells are contained within the total population of alpha 6 positive cells. <br>- BIB cells reside in the hair follicle in a region between the infundibulum and bulge and these cells are characterized by low alpha 6 integrin surface levels and are negative for CD34 and Sca-1 surface proteins. <br>- Bulge cells are derived from the bulge region of the hair follicle and are characterized by low + high alpha 6 integrin surface levels and are positive for CD34 but negative for Sca-1.
2009-11-16 | E-MEXP-928 | biostudies-arrayexpress
Project description:Continuous cell renewal in mouse epidermis is at the expense of a pool of pluripotent cells that lie in a well defined niche in the hair follicle known as the bulge. To identify mechanisms controlling hair follicle stem cell homeostasis, we developed a strategy to isolate adult bulge stem cells in mice and to define their transcriptional profile. We observed that a large number of transcripts are underexpressed in hair follicle stem cells when compared to non-stem cells. Importantly, the majority of these downregulated genes are involved in cell cycle. Using bioinformatics tools, we identified the E2F transcription factor family as a potential element involved in the regulation of these transcripts. To determine their functional role, we used engineered mice lacking Rb gene in epidermis, which showed increased expression of most E2F family members and increased E2F transcriptional activity. Experiments designed to analyze epidermal stem cell functionality (i.e.: hair regrowth and wound healing) imply a role of the Rb-E2F axis in the control of stem cell quiescence in epidermis. Total RNA was prepared from CD34+ and CD34- keratinocytes obtained from pools of at least six mice per MACS isolation procedure. A total of three isolation procedures were performed. RNA extracted from each fraction (CD34+ / CD34-) was assessed for its quality using Agilent 2100 Bioanalyzer (Agilent Technologies) and hybridized to two Affymetrix Mouse 430 2.0 arrays, to ensure reproducibility of the process. This resulted in a total of 12 chips (6 CD34+ / 6 CD34-).
2010-03-20 | E-GEOD-19448 | biostudies-arrayexpress