Premature senescence and increased oxidative stress in the thymus of Down Syndrome patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE167021 | GEO | 2021/12/24
REPOSITORIES: GEO
Similar Datasets
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 network of thymic stromal cells provides essential niches with unique molecular cues controlling T-cell development and selection. Recent single-cell RNA-sequencing studies uncovered a large transcriptional heterogeneity among thymic epithelial cells (TEC) demonstrating a previously unappreciated complexity. However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here we deconvoluted by massively parallel flow cytometry and machine learning known and novel TEC phenotypes into novel subpopulations and related these by CITEseq to the corresponding TEC subtypes defined by the cells’ individual RNA profiles. This approach phenotypically identified perinatal cTEC, physically located these cells within the cortical stromal scaffold, displayed their dynamic change during the life course and revealed their exceptional efficiency in positively selecting immature thymocytes. Collectively, we have identified novel markers that allow for an unprecedented dissection of the thymus stromal complexity, the cells physical isolation and assignment of specific functions to individual TEC subpopulations.
2023-05-24 | GSE215418 | GEO
Project description:The network of thymic stromal cells provides essential niches with unique molecular cues controlling T-cell development and selection. Recent single-cell RNA-sequencing studies uncovered a large transcriptional heterogeneity among thymic epithelial cells (TEC) demonstrating a previously unappreciated complexity. However, there are only very few cell markers that allow a comparable phenotypic identification of TEC. Here we deconvoluted by massively parallel flow cytometry and machine learning known and novel TEC phenotypes into novel subpopulations and related these by CITEseq to the corresponding TEC subtypes defined by the cells’ individual RNA profiles. This approach phenotypically identified perinatal cTEC, physically located these cells within the cortical stromal scaffold, displayed their dynamic change during the life course and revealed their exceptional efficiency in positively selecting immature thymocytes. Collectively, we have identified novel markers that allow for an unprecedented dissection of the thymus stromal complexity, the cells physical isolation and assignment of specific functions to individual TEC subpopulations.
2023-05-17 | GSE226128 | 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.
2015-07-28 | GSE68674 | GEO
Project description:BACKGROUND: The thymus is a central lymphoid organ, in which bone marrow-derived T cell precursors undergo a complex process of maturation. Developing thymocytes interact with thymic microenvironment in a defined spatial order. A component of thymic microenvironment the thymic epithelial cells (TEC) are crucial for the maturation of T-lymphocytes because the secretion of extracellular matrix compounds, thymic hormones and cytokines and also by cell-cell contacts which can be mediated by extracellular matrix compounds and its receptors, integrins. There is evidence that extracellular matrix molecules play a fundamental role in localizing the different thymocyte stages in the thymus. The interaction between alpha5beta1 (CD49e/CD29; VLA-5) and fibronectin is essential for thymocyte adhesion. Previous results from our laboratory have shown that adhesion of thymocytes to cultured TEC line is enhanced in the presence of fibronectin. And we also demonstrated that anti-VLA-5 antibody when applied to growing TEC prior to the co-culturing with thymocytes, significantly prevented their adhesion to the epithelial. RESULTS: Herein, we studied the role of integrin alpha5 subunit in thymocyte and thymic epithelial cell interactions. We investigate the in vitro effects of silencing alpha5 integrin subunit in human thymic epithelial cell line by RNA interference. After silence a great deal of interest has arisen on intracellular signaling due the absence of alpha5 integrin subunit silence. The expression profile using cDNA microarrays of alpha5 subunit silenced cells showed 131 genes differential expression. Our data showed downregulation in two genes with cell adhesion function: neuronal cell adhesion molecule (NrCAM) and Activin receptor-like kinase 1 gene and in genes related with integrin pathway like, Phosphatidylinositol-4-phosphate 5-kinase, Phospholipase C gamma1 and SHC (Src homology 2 domain containing) transforming protein 1. We also assessed the effect of the loss of alpha5beta1 expression on TEC-thymocytes interaction and ours experiments confirm that alpha5beta1 contribute to adhesion rate. CONCLUSION: Conjointly, our data reinforce the importance of VLA-5 in TEC thymocyte interactions in the process of thymocyte differentiation and we hypothesize a decrease in stress fibers due absence of alpha5 integrin subunit and a compensatory pathway because of downregulation of neuropilin-2, vascular endothelial growth factor and plexin A.
2010-02-28 | GSE18116 | 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 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
Project description:Down syndrome (DS) patients frequently develop organ-specific autoimmune disorders, particularly endocrinopathies and coeliac disease, as well as an increased susceptibility to mucosal candidiasis. These clinical features resemble APECED (autoimmune-polyendocrinopathy-candidiasis-ectodermal-dystrophy), a monogenic condition due to mutations in the AIRE gene, located on 21q22.3 and already described as down-regulated in 21 trisomy. Here we investigated AIRE expression and global gene expression profiles in surgically removed thymuses from 14 DS infants and children with congenital heart defects and from 42 age-matched individuals with cardiac defect as an isolated malformation. Immunohistochemistry revealed significantly reduced AIRE expression in DS thymuses (70.48M-BM-149.59 positive cells/mm2 in DS X 154.70M-BM-161.16 in controls, p<0.0001). qPCR confirmed the lower expression of AIRE in DS thymuses. Global thymic RNA profiles from DS patients and controls revealed 407 genes significantly hypoexpressed in DS. Network transcriptional analysis showed that hypoexpressed genes are related to biological processes such as antigen processing and presentation of endogenous antigen (ERAP2, CD1D), negative (PRDX2) and positive (CD3D, CD74) thymic T-cell selection and homeostasis of number of cells (PRDX2). Altogether these findings may explain the high prevalence of autoimmune phenomena in DS patients. Moreover, our data are in accordance with previous findings of thymic abnormal development in DS patients, characterized by lymphocyte depletion, diminution of the cortex, and loss of corticomedullary demarcation. Global gene profiles indicate that in DS patients, the trisomic imbalance probably leads to thymic hypofunction. In conclusion, lower AIRE expression and the impairment of other crucial pathways for central tolerance could well explain the high prevalence of organ-specific autoimmune disorders in DS. Among the 14 DS infants and 42 age-matched individuals with cardiac defect, only 4 from each group provided enough biological material (thymus fragments) for isolation of high-quality RNA to perform array analysis. Eight thymic samples were analyzed: C1, C2, C3 and C4 are controls, and D1, D2, D3 and D4 are from patients with Down syndrome.
2011-11-28 | E-GEOD-23910 | biostudies-arrayexpress
Project description:In the earliest step of thymic organogenesis, mesenchymal cells support the growth of thymic epithelial cells (TECs). It is established that TECs and thymocytes influence each other for their growth/differentiation, a process called thymic crosstalk. However, little is known about the influence of developing thymocytes or TECs on mesenchymal cells. Here, we show that during normal thymus development fibroblast ingrowth occurs towards hypoxic areas. Similar overgrowth of mesenchymal cells is seen in a fetal thymic organ culture system under low oxygen conditions. However, when thymocytes were depleted by deoxyguanosine treatment, mesenchymal cells were also induced, precluding the direct effect of hypoxia. In the fetal thymus of hCD3εTg mice, which lack T lineage cells, an overgrowth of mesenchymal cells can be seen at a very early stage of thymic organogenesis. The growth of the mesenchymal cells is due to extensive proliferation and not mere enrichment. With RNA sequencing analysis comparing hCD3εTg with wild type TECs, we identified candidate factors that could be involved in mesenchymal network formation.
2017-08-19 | GSE60520 | GEO
Project description:The thymus is a primary lymphoid organ necessary for optimal T cell development. Here we show that liver X receptors, which are a class of nuclear receptors and transcription factors with diverse functions in metabolism and immunity, critically contribute to thymic integrity and function. LXRαβ-deficient mice develop a fatty, rapidly-involuting thymus, and acquire a shrunken and prematurely senescent peripheral T cell repertoire. The functions of LXRαβ are cell specific and the resulting phenotypes mutually independent. Whereas macrophages require LXRαβ for reverse cholesterol transport and lipid removal, thymic epithelial cells (TEC) and thymocytes respectively utilize LXRαβ for self-renewal and negative selection. Consequently, TEC-derived LXRαβ protect against premature involution in homeostasis and orchestrate thymic regeneration following stress, while thymocyte-derived LXRαβ limit cell disposal during negative selection and confer heightened sensitivity to experimental autoimmune encephalomyelitis. These results identify three distinct but complementary mechanisms by which LXRαβ govern T lymphocyte education.
2020-01-29 | GSE144342 | GEO