Single-cell RNA sequencing of non-hematopoietic cells from mouse thymus spanning embryonic and adult stages
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE192480 | GEO | 2022/03/17
REPOSITORIES: GEO
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Project description:TEC progenitors that express beta 5-t contribute to both the cortical and medullary TEC compartments. Our initial experiments across ageing thymi identified a population of potential progenitor TECs which expanded with age, and appears to be a progenitor population for mTEC. These lineage tracing experiments are designed to chart the altered differentiation and senescence of mTEC progenitors with age.
2020-09-14 | E-MTAB-8737 | biostudies-arrayexpress
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: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:Here we describe a universal direct differentiation protocol that allows the generation of thymic epithelial progenitor cells (TEPs) from different iPSC lines. Upon transplantation into an athymic mouse model, TEPs further differentiate into thymic epithelial cells (TECs). TECs are functional and can facilitate the education of developing mouse T-cells. iPSC derived, patient specific TECs residing within grafts are indistinguishable from TECs present in human primary neonatal thymus tissue as revealed by single cell RNA sequencing analysis indicating the generation of a mature TEC phenotype. Taken together, we provide a universal direct differentiation protocol that generates TEPs from all iPSC lines tested, that can further differentiate into mature, functional TECs. We anticipate that these findings have important implications for current efforts aimed at generating a functional human thymus.
2021-09-24 | GSE148495 | GEO
Project description:Thymic T cell development and T cell antigen receptor repertoire selection are dependent on essential molecular cues provided by thymic epithelial cells (TECs). These cells rely for their development and function on the correct placement of post-translational histone modifications. The repressive H3K27me3 mark is catalyzed by the holoenzyme Polycomb Repressive Complex 2 (PRC2). Mice with a TEC-targeted deficiency of PRC2 are differentially affected in their TEC lineage development establishing a novel differentiation path that progressively off-sets the shortage of canonical medullary TEC. The resultant hypoplastic thymus is severely compromised in its ability present antigen and to select a repertoire of T cells with normal effector and regulatory functions. A heightened peripheral activation of regulatory T cells, however, prevents the occurrence of overt autoimmunity in these mice.
2021-02-19 | GSE112050 | GEO
Project description:Purpose: In all vertebrates, the thymus is necessary and sufficient for production of classic adaptive T cells. The key components of the thymus are cortical and medullary thymic epithelial cells (cTECs and mTECs). Despite the capital role of TECs, our understanding of TEC biology is quite rudimentary. For instance, we ignore what might be the extent of divergence in the functional program of these two TECs populations. It also remains unclear why the number of TECs decreases rapidly with age, thereby leading to progressive thymic insufficiency. Methods: Systems level understanding of cell function begins with gene expression profiling, and the transcriptome is currently the only '-ome' that can be reliably tackled in its entirety in freshly harvested primary cells. In order to gain novel insights into TEC biology, we therefore decided to analyse the whole transcriptome of cTECs, mTECs and skin epithelial cells. We elected to analyse gene expression using RNA-seq rather microarrays because RNA-seq has higher sensitivity and dynamic range coupled to lower technical variations. Results: Our deep sequencing approach provides a unique perspective into the transcriptome of TECs. Consistent with their ability to express ectopic genes, we found that mTECs expressed more genes than other cell populations. Out of a total of 15,069 genes expressed in TECs, 25% were differentially expressed by at least 5-fold in cTECs vs. mTECs. Genes expressed at higher levels in cTECs than mTECs regulate numerous cell functions including cell differentiation, cell movement and microtubule dynamics. Almost all positive regulators of the cell cycle were overexpressed in skin ECs relative to TECs. Conclusions: Our RNA-seq data provide novel insights into the transcriptional landscape of TECs, highlight substantial divergences in the transcriptome of TEC subsets and suggest that cell cycle progression is differentially regulated in TECS and skinECs. We believe that our work will therefore represent a valuable resource and will be of great interest to readers working in biological sciences, particularly in the areas of immunology and systems biology. The mRNA profiles of cTEC, mTEC (from 14 thymi of 7-days old C57BL/6 mice) and skinEC (from the trunk and dorsum of seven newborn mice) were generated by RNA-sequencing using Illumina HiSeq2000.
2013-05-07 | E-GEOD-44945 | biostudies-arrayexpress
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
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 | GSE249752 | GEO
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
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 | GSE240016 | GEO