Expression data from thymic non-hematopoietic stromal cells after damage
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE106981 | GEO | 2018/02/01
REPOSITORIES: GEO
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Project description:The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. To identify alternate regeneration pathways in the thymus, we performed an unbiased transcriptome analysis of the non-hematopoietic (CD45-) stromal cell compartment of the thymus, which is less sensitive to thymic damage compared to the CD45+ hematopoietic compartment.
2021-10-01 | GSE160989 | GEO
Project description:The thymus is extremely sensitive to damage but also has a remarkable ability to repair itself. However, the mechanisms underlying this endogenous regeneration remain poorly understood and this capacity diminishes considerably with age. To identify alternate regeneration pathways in the thymus, we performed an unbiased transcriptome analysis of the non-hematopoietic (CD45-) stromal cell compartment of the thymus, which is less sensitive to thymic damage compared to the CD45+ hematopoietic compartment. Recent work has suggested that ECs can contribute towards thymic regeneration via their production of so-called angiocrine factors. Using a technique to constitutively activate the Akt pathway in ECs using the pro-survival adenoviral gene E4ORF1, ECs can be propagated and expanded ex vivo (exEC) while maintaining their phenotype and vascular tube formation capacity. We compared the gene expression of freshly isolated thymic ECs and exEC-derived from the thymus.
2018-02-01 | GSE106980 | GEO
Project description:Thymic epithelial cells (TECs) support T cell development in the thymus. Cortical thymic epithelial cells (cTECs) facilitate positive selection of developing thymocytes whereas medullary thymic epithelial cells (mTECs) facilitate the deletion of self-reactive thymocytes in order to prevent autoimmunity. The mTEC compartment is highly dynamic with continuous maturation and turnover, but the genetic regulation of these processes remains poorly understood. MicroRNAs (miRNAs) are important regulators of TEC genetic programs since miRNA-deficient TECs are severely defective. However, the individual miRNAs important for TEC maintenance and function and their mechanisms of action remain unknown. Here, we demonstrate that miR-205 is highly and preferentially expressed in mTECs during both thymic ontogeny and in the postnatal thymus. This distinct expression is suggestive of functional importance for TEC biology. Genetic ablation of miR-205 in TECs, however, neither revealed a role for miR-205 in TEC function during homeostatic conditions nor during recovery from thymic stress conditions. Thus, despite its distinct expression, miR-205 on its own is largely dispensable for mTEC biology. In order to identify miRNAs differentially expressed in mTECs, we purified cortical thymic epithelial cells (cTECs), mTECs and CD45+ cells as three distinct populations and prepared RNA for microarray analysis. Thymic subsets were FACS-purified from 4-week old NOD wildtype mice. Thymi from 10-12 female mice were pooled together for stromal cell isolation for a total of 3 CD45+, 2 cTEC and 3 mTEC biologic replicates.
2015-07-28 | E-GEOD-68674 | biostudies-arrayexpress
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:Human T lymphogenesis includes emergence, migration and thymus-seeding of T lymphoid precursor, followed by T-lymphocytes commitment in thymus, which are largely unknown. Here, we perform single-cell RNA sequencing using cells isolated from human hemogenic/hematopoietic sites such as aorto-gonad-mesonephros (AGM), liver, and thymic primordia spanning embryonic and fetal stages. The transcriptional atlas of thymic primordia illustrates the cellular trajectory of early T-lymphocyte development. Further, thymic seeding progenitors in liver and unique T lymphoid progenitors in AGM at CS14, are first unveiled. We also reveal the stepwise-specification of thymic epithelial cells，and the potential cell-cell interactions between T-lymphocyte progenitors and stromal cells during thymus organogenesis. Our data provide new insights into T lymphogenesis, which prospectively directs the efficient regeneration of T- lymphocytes from pluripotent stem cells
2019-10-09 | GSE133341 | GEO
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
Project description:The mechanism of egress of mature regulatory T cells (Tregs) from the thymus to the periphery remains enigmatic, as does the nature of those factors expressed in the thymic environment. Here, we examined the fate of thymic Tregs in TNFα/RelA double-knockout (TA-KO) mice, because TA-KO mice retain a Treg population in the thymus but have only a small Treg population at the periphery. Transplantation of whole TA-KO thymus to under the kidney capsule of Rag1 null mice failed to induce the production of donor-derived splenic Tregs expressing neuropilin-1 (Nrp1), which was reported to be a marker of naturally occurring Tregs, indicating that TA-KO thymic Tregs either do not leave the thymus or are lost at the periphery. We next transplanted enriched TA-KO thymic Tregs to the peripheries of TA-KO mice and traced mouse survival. Transplantation of TA-KO thymic Tregs rescued the lethality in TA-KO mice, demonstrating that TA-KO thymic Tregs remain functional at the periphery. The TA-KO thymic Treg population had highly demethylated CpG motifs in the foxp3 locus, indicating that the cells were arrested at a late-mature stage. Also, the population included a large subpopulation of Tregs expressing IL-7Rα, which is a possible marker of late-mature Tregs. Finally, TA-KO fetal liver chimeric mice developed an Nrp1+ splenic Treg population from TA-KO cells, suggesting that Treg arrest is caused by a lack of RelA in the thymic environment. Together, these results suggest that egress of mature Tregs from the thymus depends on RelA in the thymic environment. For the isolation of thymic Tregs, CD4+CD8α-CD25hi thymocytes were isolated from five 1.5- to 2-week-old TNFα-KO or TA-KO mice by using a FACSAria cell sorter. For the isolation of thymic stromal cells, 10 thymi from 1.5- to 2-week-old TNFα-KO or TA-KO mice were minced with scissors and treated with RPMI 1640 supplemented with 2% FCS, 0.2 mg/ml collagenase (Roche, Basel, Switzerland), 0.2 mg/ml dispase I (Roche), and 100 U/ml DNase I (Life Technologies) for 30 min with stirring. Digested thymi were centrifuged in a Percoll (GE Healthcare Bio-Sciences, Piscataway, NJ, USA) gradient (density, 1.115, 1.065, and PBS) at 1400g for 30 min. Cells in the upper layer were collected, and the CD45-EpCAM+ (thymic epithelial cells) and CD45+EpCAM- populations (enriched thymic stromal cells containing macrophages or dendritic cells) were sorted.
2015-03-04 | E-GEOD-64191 | biostudies-arrayexpress
Project description:The generation of new naive T-cells is dependent on thymic output, but in adults the naive T-cell pool is primarily maintained by peripheral proliferation. Naive T-cells have long been regarded as relatively quiescent cells but recently it was shown that IL-8 production is a signatory effector function of naïve T-cells, at least in newborns. With human aging naïve CD4 T-cell numbers decline but it is not clear whether this is accompanied by (functional) differentiation of naïve T-cells and loss of true naivety. Using a unique cohort of children and adolescents who underwent neonatal thymectomy, we demonstrate that the naive CD4 T-cell compartment in healthy humans is functionally heterogeneous and that this functional diversity is lost after neonatal thymectomy. Thymic regeneration later in life resulted in functional restoration of the naïve T-cell compartment. These data shed further light on functional differentiation within the naive T-cell compartment and the importance of the thymus in naive T-cell homeostasis.
2016-10-18 | GSE72400 | GEO
Project description:Thymic epithelium is critical for the structural integrity of the thymus and for T cell development. Within the fully formed thymus, large numbers of hematopoietic cells shape the thymic epithelium into a scaffold-like structure which bears little similarity to classical epithelial layers, such as those observed in the skin, intestine or pancreas. Here, we show that human thymic epithelial cells (TECs) possess an epithelial identity that also incorporates the expression of mesenchymal cell associated genes, whose expression levels vary between medullary and cortical TECs (m/cTECs). Using pluripotent stem cell (PSC) differentiation systems, we identified a unique population of cells that co-expressed the master TEC transcription factor FOXN1, as well as the epithelial associated marker EPCAM and the mesenchymal associated gene CD90. Using the same serum free culture conditions, we also observed co-expression of EPCAM and CD90 on cultured TECs derived from neonatal human thymus in vitro. Single cell RNA-sequencing revealed these cultured TECs possessed an immature mTEC phenotype and expressed epithelial and mesenchymal associated genes, such as EPCAM, CLDN4, CD90 and COL1A1. Importantly, flow cytometry and single cell RNA-sequencing analysis further confirmed the presence of an EPCAM+CD90+ population in the CD45- fraction of neonatal human thymic stromal cells in vivo. Using the human thymus cell atlas, we found that cTECs displayed more pronounced mesenchymal characteristics than mTECs during embryonic development. Collectively, these results suggest human TECs possess a hybrid gene expression program comprising both epithelial and mesenchymal elements, and provide a basis for the further exploration of thymus development from primary tissues and from the in vitro differentiation of PSCs.
2022-02-28 | GSE196005 | GEO
Project description:The thymic stroma provides the microenvironment for T cell lineage commitment, development, maturation, and repertoire selection. While the thymic epithelial cell (TEC) compartment is relatively well characterised, a comparably detailed analysis of the non-TEC stromal compartment including the endothelial cells and fibroblasts is currently lacking. Here, we probe the composition of thymic mesenchymal cells and their dynamic change during thymus organogenesis. Using a single cell transcriptomic approach, we identify previously unappreciated heterogeneity within the non-TEC stromal compartment and demonstrate dynamic shifts within non-TEC stromal cell populations over thymic development. We then use a compound heterozygous model (Tbx1+/-Crkl+/-) for 22q11.2DS syndrome to show that significant reductions of multiple mesenchymal subpopulations associated with functional defects and accelerated aging are associated with the thymic hypoplasia observed in this condition. Thus, we provided a comprehensive picture of non-TEC thymic stromal development and their functional defects in a disease model of thymic hypoplasia.
2022-05-13 | GSE163520 | GEO