Global transcriptional profiling reveals distinct functions of thymic stromal subsets and age-related changes during thymic involution
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE56928 | GEO | 2014/09/12
SECONDARY ACCESSION(S): PRJNA244976
REPOSITORIES: GEO
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Project description:The thymic microenvironment is essential for proper differentiation and selection of thymocytes.Thymic involution in aged mice results in decreased T cell output and immune function. Here we use gene expression profiling of FACS sorted thymic stromal subsets to identify molecular mediators of thymocyte: stromal cell interactions, as well as gene expression changes thymic stromal subsets during early stages of thymic involution . We used microarrays to analyze gene expression differences between thymic stromal subsets from male C57BL/6J mice 1, 3, and 6 months of age. Thymic stromal subsets (cTEC, mTEClo, mTEChi, Sirpa-DC, Sirpa+DC, and fibroblasts) were isolated from two 1-, 3-, and 6- month old male C57BL/6J mice. After enzymatic digestion of the thymi, the stromal cells were FACS purified, and RNA was extracted, amplified, labeled and hybridized to Affymetrix mouse 430 2.0 arraysarrays. Raw data were uploaded to Gene Expression Commons for normalization. Both raw CEL and normalized datasets from the 36 samples are included. A model within Gene Expression Commons has been created for analyses/comparisons of these datasets, along with previously reported thymocyte subset datasets. The model within Gene Expression Commons thus contains 6 thymic stromal populations, each from mice 1, 3, and 6 months of age, with duplicates for each datset.
2014-09-12 | E-GEOD-56928 | biostudies-arrayexpress
Project description:Given its central role in immune aging, identifying regulators of thymic involution is important. While conventional programmed cell death plays a fundamental role in thymocyte development, how cell death pathways contribute to thymic involution remains unclear. In this study, we found that CD4+CD8+ double positive (DP) thymocytes acquired characteristics of senescence in aged mice undergoing thymic involution, while expression of the m6A methyltransferase METTL3 (enriched in DP cells from young mice) decreased with aging. By conditionally deleting METTL3 in T cells, we revealed a critical role for METTL3 in DP cell survival, and in restraining features of aging in DP thymocytes by preventing ferroptosis signaling, through glutathione peroxidase 4 (GPX4). Mechanistically, GPX4 was maintained by METTL3 at the translational level, independent of its methyltransferase activity. Furthermore, we found that pharmacological inhibition of ferroptosis promoted DP cell survival, and attenuate d features of aging in DP thymocytes. These findings uncover a role for METTL3-regulated ferroptosis in thymic involution, and identify strategies to restore thymic function.
2024-08-18 | GSE271324 | GEO
Project description:METTL3 governs thymocyte development and thymic involution by regulating ferroptosis
| PRJNA1130936 | ENA
Project description:During gestation, sex hormones cause a significant thymic involution which enhances fertility. This thymic involution is rapidly corrected following parturition. As thymic epithelial cells (TECs) are responsible for the regulation of thymopoiesis, we analyzed the sequential phenotypic and transcriptomic changes in TECs during the postpartum period in order to identify mechanisms triggering postpartum thymic regeneration. In particular, we performed flow cytometry analyses and deep RNA-sequencing on purified TEC subsets at several time points before and after parturition. We report that pregnancy-induced involution is not caused by loss of TECs since their number does not change during or after pregnancy. However, during pregnancy, we observed a significant depletion of all thymocyte subsets downstream of the double-negative 1 (DN1) differentiation stage. Variations in thymocyte numbers correlated with conspicuous changes in the transcriptome of cortical TECs (cTECs). The transcriptomic changes affected predominantly cTEC expression of Foxn1, its targets and several genes that are essential for thymopoiesis. By contrast, medullary TECs (mTECs) showed very little transcriptomic changes in the early postpartum regenerative phase, but seemed to respond to the expansion of single-positive (SP) thymocytes in the late phase of regeneration. Together, these results show that postpartum thymic regeneration is orchestrated by variations in expression of a well-defined subset of cTEC genes, that occur very early after parturition.
2019-11-20 | GSE138494 | GEO
Project description:The thymus is the site of T lymphocyte development and T cell education to recognize foreign, but not self, antigens. B cells also reside and develop in the thymus, although their function(s) are less clear. During ‘thymic involution,’ a process of lymphoid atrophy and adipose replacement linked to sexual maturation, thymic cells decline. However, thymic B cells decrease far less than T cells, such that B cells comprise ~1% of neonatal thymocytes, but up to ~10% in adulthood in humans. All jawed vertebrates possess a thymus, and we and others have shown that zebrafish (Danio rerio) also have thymic B cells. Here, we investigated the precise identities of zebrafish thymic T and B cells and how they change with involution. We assessed the timing and specific details of zebrafish thymic involution using multiple lymphocyte-specific, fluorophore-labeled transgenic lines, quantifying changes in thymic lymphocytes pre- vs. post-involution. Our results prove that, as in humans, zebrafish thymic B cells increase relative to T cells post-involution. We also performed RNA sequencing (RNA-seq) on D. rerio thymic and marrow lymphocytes of four novel double-transgenic lines, identifying distinct populations of immature T and B cells. Collectively, this is the first comprehensive analysis of zebrafish thymic involution, demonstrating its similarity to human involution, and establishing the highly genetically-manipulatable zebrafish model as a template for involution studies.
2024-04-02 | GSE237139 | GEO
Project description:Transcriptome analysis was performed on the thymus of necropsied Japanese Black calves with a poor prognosis, to clarify the pathology of acute thymic involution, which often happens in farmed calves with a poor prognosis. Gene expression profiles obtained by DNA microarray analysis of eight calf thymuses were grouped into three patterns associated with the histopathological classification of acute thymic involution. Three clusters were arranged by the stage of acute thymic involution based on the first principal component score, suggesting that histopathological conditions have the most significant impact on changes in gene expression profile.
2024-08-18 | GSE269843 | GEO
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
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
Project description:The decline in adaptive immunity, naïve T-cell output and a contraction in the peripheral T cell receptor (TCR) repertoire with age are largely attributable to thymic involution and the loss of critical cytokines and hormones within the thymic microenvironment. To assess the molecular changes associated with this loss of thymic function, we used cDNA microarray analyses to examine the transcriptomes of thymocytes from mice of various ages ranging from very young (1 month) to very old (24 months). Genes associated with various biological and molecular processes including oxidative phosphorylation, T- and B- cell receptor signaling and antigen presentation were observed to significantly change with thymocyte age. These include several immunoglobulin chains, chemokine and ribosomal proteins, annexin A2, vav 1 and several S100 signaling proteins. The increased expression of immunoglobulin genes in aged thymocytes could be attributed to the thymic B cells which were found to be actively producing IgG and IgM antibodies. Upon further examination, we found that purified thymic T cells derived from aged but not young thymi also exhibited IgM on their cell surface suggesting the possible presence of auto-antibodies on the surface thymocytes with advancing age. These studies provide valuable insight into the cellular and molecular mechanisms associated with thymic aging. Keywords: Thymocytes, thymic involution, aging, time course 3 replicates each from the 6, 16 and 24 month old animals were labeled with Cy-3 and hybridized with a Cy-5 labeled pool from 1 month old mice. The data from the 2 channels are being reported here separately.
2009-05-05 | E-GEOD-15945 | biostudies-arrayexpress
Project description:Despite their key role in immunity our understanding of primary and secondary lymphoid stromal cell heterogeneity and ontogeny remains limited. Here, using genome-wide expression profiling and phenotypic and localization studies, we identify a functionally distinct subset of BP3-PDPN+PDGFRβ+/α+CD34+ stromal adventitial cells in both lymph nodes and thymus that is located within the perivascular niche surrounding PDPN-PDGFRβ+/α-Esam-1+ITGA7+ pericytes. In re-aggregate organ grafts adult CD34+ adventitial cells gave rise to multiple thymic and lymph node mesenchymal subsets including pericytes, FRC-, MRC- and FDC-like cells, the development of which was lymphoid environment dependent. During thymic ontogeny pericytes developed from a transient population of BP3-PDPN+PDGFRβ+/α+CD34-/lo anlage-seeding progenitors that subsequently up-regulated CD34 and we provide evidence suggesting that similar embryonic progenitors give rise to lymph node mesenchymal subsets. These findings extend the current understanding of lymphoid mesenchymal cell heterogeneity and highlight a role of the CD34+ vascular adventitia as a potential ubiquitous source of lymphoid stromal precursors in postnatal tissues. To comprehensively study the differences and similarities between mesenchymal stromal subsets in the thymus and lymph nodes, global gene expression analysis was performed on sorted PDPN-, BP-3-PDPN+ and BP-3+PDPN+ PDGFRb+ lymph node mesenchymal cells (LNMC) as well as PDPN- and BP-3-PDPN+ PDGFRb+ thymic mesenchymal cells (TMC) from 2 w old mice by microarray. Total RNA was prepared from TMC and LNMC (pooled inguinal, brachial and axillary LN) subsets sorted from 3 (TMC) and 10-11 (LNMC) 2 weeks old mice per experiment. Isolated RNA from 3 individual experiments was amplified and prepared for hybridization to the Affymetrix Mouse Gene 1.1 ST Array at a genomics core facility: Center of Excellence for Fluorescent Bioanalytics (KFB, University of Regensburg, Germany)
2016-03-03 | E-GEOD-76974 | biostudies-arrayexpress