Thymic epithelial cells induce formation of mesenchymal network structure after abrogation of thymic crosstalk
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE60520 | GEO | 2017/08/19
SECONDARY ACCESSION(S): PRJNA258460
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: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: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:Thymic epithelial cells (TECs) begin to develop embryonically in mice and humans, expand in number through puberty, and then stabilize before declining during early adulthood. We identified a mechanism by which TEC numbers and function are maintained postnatally, discovered through a forward genetic screen for altered immune cell development in mice. A viable missense allele (C120Y) of Ovol2 resulted in lymphopenia, in which T cell development was compromised by loss of medullary TECs and dysfunction of cortical TECs. OVOL2 is an essential regulator of epithelial to mesenchymal transition (EMT), and we show that the epithelial identity of TECs is subverted towards a mesenchymal state in OVOL2-deficient mice. We document global changes in chromatin accessibility correlated with gene expression, particularly affecting genes involved in epithelial and mesenchymal cell proliferation and differentiation. OVOL2 regulates chromatin accessibility by inhibiting the BRAF-HDAC complex. In particular, it disrupts the RCOR1-LSD1 complex by directly binding to the lysine demethylase LSD1, resulting in inhibition of LSD1-mediated H3K4me2 demethylation. Thus, OVOL2 controls the epigenetic landscape of TECs, preventing EMT and enforcing TEC identity to support T cell development in the thymus.
2022-12-21 | MSV000090946 | MassIVE
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 | GSE240015 | 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
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:In this report, we show that VEGF-blockade in neonates induces rapid changes in all three stromal compartments of the thymus, and that these changes recapitulate the maturation of these cell types seen during the transition from the neonatal to the young adult thymus. These changes in the microenvironment occur prior to the loss of thymocytes, and include not only a loss of cTECs relative to mTECs but also depletion of CD146+CD140aneg cells, a novel population of pericytes we have identified in the neonatal thymus. Importantly, we show that based on receptor expression and receptor blockade, VEGF drives the fetal/neonatal phenotype of the thymus through distinct VEGFR2- and NRP1-dependent pathways in thymic endothelial and mesenchymal cells respectively. In addition, receptor signaling induces changes in critical pathways affecting the function of all three compartments, with consequences on thymopoieisis.
2020-08-31 | GSE126681 | GEO