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Age-related epithelial defects limit thymic function and regeneration [single cell]

ABSTRACT: The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.

ORGANISM(S): Mus musculus

PROVIDER: GSE240016 | GEO | 2024/06/27

REPOSITORIES: GEO

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Project description:The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in non-hematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated (aa)TECs formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of non-productive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition (EMT), and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTEC drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTEC expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune boosting therapies in older individuals.

2024-06-27 | GSE240017 | GEO

2024-06-27 | GSE240015 | GEO

2024-06-27 | GSE249753 | GEO

2024-06-27 | GSE249752 | GEO

Activation of Inflammation and Metabolic Networks in Age-related Thymic Involution.

Project description:Genetic modeling of thymic involution has demonstrated the importance of individual inflammatory pathways affecting the thymic microenvironment, particularly thymic epithelial cells (TEC). We studied the pathogenic processes in chronological aging of the murine thymus. We used microarrays to elucidate the global gene expression and to identify a leading edge subset of age-associated genes in TEC. Analyses of the TEC transcriptome demonstrated altered expression associated with inflammatory and fatty acid metabolism.

2016-05-06 | GSE81163 | GEO

Transcriptome analysis of thymic epithelial cells and thymic non-epithelial stromal cells from young, middle-aged and castrated middle-aged male mice

Project description:The thymus is primarily responsible for generating naïve, self-tolerant T cells from hematopoietic precursors. Thymic epithelial cells (TECs) together with other stromal cells create a specialized microenvironment which orchestrates the major selection processes for T cell development. Thymic function progressively deteriorates as part of the aging process, with a dramatic loss in TECs and T cell production, and this ultimately constrains the host immune repertoire. We have previously demonstrated the role of sex steroids in thymic involution in male mice, with surgical castration of middle-aged (9-12 month) male mice resulting in thymus regeneration, peaking around day 28. We have also demonstrated phenotypic alterations in TEC subsets within one week following castration that may contribute to this transient thymus regeneration effect. In this study, we aimed to examine genetic alterations in TEC and non-TEC stromal cell subsets (predominantly fibroblasts and endothelial cells) during age-related thymic involution (5-6 week old young adults compared to 9-12 month middle aged); and genetic changes in TEC and non-TEC at several timepoints following castration, to identify factors that may be involved in thymus regeneration.

2019-06-06 | GSE132278 | GEO

Next-generation sequencing of cTEC and mTEC isolated from non-pregnant and pregnant females lacking the expression of Klf4 (KO) or not (LOX)

Project description:Stress-induced thymic involution is defined by profound damage to thymic epithelial cells (TECs), resulting in an acute and transient reduction of thymopoietic capacity. During pregnancy, thymic involution is not associated with TEC loss but rather with TEC quality modifications. Study of the mechanisms of TEC maintenance during pregnancy may be of critical importance for identifying new players for thymic regeneration in other models of thymic involution. We report a strong enrichment for motifs recognized by KLF4 based on genes differentially expressed in TECs of pregnant females. Therefore, we studied the impact of Klf4 deletion in TECs during pregnancy by analyzing thymus composition and TEC transcriptome. Conditional Klf4 deletion in homeostatic conditions does not injure thymic integrity. However, pregnant females lacking Klf4 show a disrupted thymus with substantial loss of thymic epithelial cells. Klf4 maintains cTEC number during pregnancy by maintaining cell survival and inhibiting the transition to a mesenchymal state. Our study reveals Klf4 as a protective factor for TECs during pregnancy-associated thymic involution and represents a potential study subject for other models of stress-induced thymic involution.

2022-09-30 | GSE210885 | GEO

Tuft cells and fibroblasts promote thymus regeneration through activation of a type-2 immune response [TEC_after_rAREG_inj]

Project description:The goal of this study was to determine how thymic epithelial cells (TEC) differentiation and gene expression is affected by amphiregulin (AREG), which is produced by ILC2 upon thymic involution and the receptor for which is expressed by early TEC subsets. For this purpose we treated WT mice with recombinant AREG, sorted TEC from their thymi 10 days after treatment when the thymus is recovering and AREG has been released, and performed bulk RNA-Seq.

2024-01-11 | GSE244225 | GEO

Single-cell RNA-sequencing of mouse thymic epithelial cells across the first year of life

Project description:The thymus shapes the T cell receptor repertoire, and is one of the first organs to rapidly age, with gross changes in cellularity and architecture. To resolve the nature of these changes we used SMART-Seq2 on FACS purified thymic epithelial cells (TEC) across the first year of mouse life. We sorted 4 TEC populations in each of 5 mice at each age (1 week, 4 weeks, 16 weeks, 32 weeks and 52 weeks old).

2020-09-14 | E-MTAB-8560 | biostudies-arrayexpress

Large-scale single cell mapping of the thymic stroma identifies a new thymic epithelial cell lineage [ChIP-seq]

Project description:T cell development and selection is orchestrated in the thymus by a specialized niche of diverse stromal populations. By transcriptional single cell sorting, we de novo characterize the entire stromal compartment of the thymus. We identified dozens of cell states within the thymic stroma, with thymic epithelial cells (TEC) showing the highest degree of heterogeneity. Our analysis highlights four major medullary TEC (mTEC I-IV) populations, with distinct molecular functions, epigenetic landscapes and lineage regulators. Specifically, mTEC-IV constitutes a new and highly divergent TEC lineage with molecular characteristics of the gut chemosensory epithelial tuft cells. Mice deficient of Pou2f3, a tuft cells master regulator, resulted in complete and specific depletion of mTEC-IV, without affecting other TEC populations. Overall, our study comprehensively defines all stroma cells in the thymus and identifies a new TEC lineage associated with chemosensory properties that may potentially link the adaptive immune system to environmental and neurological signals.

2018-07-23 | GSE103969 | GEO

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