Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

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: GSE240017 | GEO | 2024/06/27

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

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 | GSE249753 | GEO

2024-06-27 | GSE249752 | GEO

2024-06-27 | GSE240016 | GEO

2024-06-27 | GSE240015 | GEO

Single-cell RNA sequencing of thymic EC and TEC from control and RANKL treated aged mice

Project description:Age-related thymic involution is one of the major causes of immunosenescence, characterized by reduced production of naive T cells, leading to increased susceptibility to cancers, infections, autoimmunity and reduced vaccine efficacy. Here, we reveal that the RANK/RANKL axis is altered in the thymus during aging, which results in a decline in thymic epithelial cell (TEC) and endothelial cell (EC) function and, consequently, to thymic involution. Whereas RANKL neutralization in young mice mimics thymic involution, RANKL treatment in aged individuals restores the thymic architecture, TEC and EC functional properties, and thymic T-cell production. This cascade of events results in peripheral T cell renewal and effective anti-tumor and anti-viral immune responses. Furthermore, we provide the proof-of-concept that RANKL stimulates TEC and EC in human thymic organo-cultures. Collectively, our findings identify RANKL administration as a potent therapeutic strategy to rejuvenate thymic function and improve T-cell immune function in the elderly.

2024-09-30 | GSE241880 | 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