Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA114865 | ENA |
REPOSITORIES: ENA
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Project description:Hürthle cells are found in thyroid tumors and autoimmunity, and have a unique appearance characterized by swollen eosinophilic cytoplasm filled with mitochondria and hyperchromatic nucleus. The pathogenesis of Hürthle cells remains unknown. We have generated transgenic mice expressing IFNg specifically in thyroid gland, and shown they develop changes in the thyroid follicular cell that resemble those of the human Hürthle cell. Transcriptome analysis by serial analysis of gene expression revealed an increased expression of immunoproteasome subunits in transgenic thyrocytes. LMP2, an immunoproteasome subunit also known as PSMB9 or ib1, provided critical for Hürthle cells and hypothyroidism development. Transgenic mice treated with a proteasome inhibitor ameliorated the Hürthle cell phenotype, and failed to develop it when crossed to LMP2 deficient mice. LMP2 was expressed in Hürthle cells from Hashimoto thyroiditis and thyroidal cancer patients. We propose that LMP2 is a nobel therapeuetic target for Hürthle cell lesions. We used 16 wildtype female mice for "Thyroid_wildtype_CD45depleted" and 3 thyroid specific IFNg transgenic female mice for "Thyroid_IFNg_transgenic_CD45depleted". Both wildtype and transgenic mouse thyroids have hematopoiteic cells, especially transgenic mouse have numerous mononuclear cell infiltration. We purely wanted to study gene expression of thyrocytes, because Hürthle cell is a follicular cell and a majority of thyrocytes are follicular cells. A difference of number of mice between two groups are due to a difference of size of thyroid lobes (Kimura et al. Int J Exp Pathol 86, 97-106, 2005).
2009-07-01 | E-GEOD-15114 | biostudies-arrayexpress
Project description:Interferon-alpha is a major therapeutic agent for many diverse diseases. However, the interferon-alpha mechanism of therapeutic action and associated side effects are not well understood. In particular, thyroiditis is a common unexplained complication. We hypothesized that direct thyroid-toxic actions coupled with immune mechanisms play a major role in the thyroiditis etiology. To test this hypothesis, we investigated the actions of interferon-alpha on cultured thyrocytes in vitro, and in vivo by creating transgenic mice overexpressing interferon-alpha tissue specifically in thyrocytes. Interferon-alpha treatment of cultured PCCL3 rat thyrocytes increased markers of thyroid differentiation, levels of MHC class I, and expression of heat shock protein and CXCL10. This was associated with markedly increased nonapoptotic thyroid cell death. Consistent with these in vitro findings, transgenic mice overexpressing interferon-alpha in the thyroid displayed striking thyroid cell death characteristic of nonimmune thyroid destruction that progressed to profound primary hypothyroidism. Moreover, genes linked to cell death pathways, granzyme B, or known to be associated with recruitment of a cytotoxic immune response, CXCL10, interleukin-23, and TRIM21 were increased in the transgenic thyroids. Taken together, the etiology of interferon-induced thyroiditis likely involves both a direct toxic action on thyrocytes, as well as provocation of a destructive immune response. 1) Thyroid cells were incubated with interferon-alpha, and global gene expression was determined by RNA-seq. 2) Thyroid tissues were obtained from transgenic mice overexpressing interferon-alpha and from wild type mice, and global gene expression was analyzed using RNA-seq.
2011-11-03 | E-GEOD-25115 | biostudies-arrayexpress
Project description:Hürthle cells are found in thyroid tumors and autoimmunity, and have a unique appearance characterized by swollen eosinophilic cytoplasm filled with mitochondria and hyperchromatic nucleus. The pathogenesis of Hürthle cells remains unknown. We have generated transgenic mice expressing IFNg specifically in thyroid gland, and shown they develop changes in the thyroid follicular cell that resemble those of the human Hürthle cell. Transcriptome analysis by serial analysis of gene expression revealed an increased expression of immunoproteasome subunits in transgenic thyrocytes. LMP2, an immunoproteasome subunit also known as PSMB9 or ib1, provided critical for Hürthle cells and hypothyroidism development. Transgenic mice treated with a proteasome inhibitor ameliorated the Hürthle cell phenotype, and failed to develop it when crossed to LMP2 deficient mice. LMP2 was expressed in Hürthle cells from Hashimoto thyroiditis and thyroidal cancer patients. We propose that LMP2 is a nobel therapeuetic target for Hürthle cell lesions.
2009-07-01 | GSE15114 | GEO
Project description:Interferon-alpha is a major therapeutic agent for many diverse diseases. However, the interferon-alpha mechanism of therapeutic action and associated side effects are not well understood. In particular, thyroiditis is a common unexplained complication. We hypothesized that direct thyroid-toxic actions coupled with immune mechanisms play a major role in the thyroiditis etiology. To test this hypothesis, we investigated the actions of interferon-alpha on cultured thyrocytes in vitro, and in vivo by creating transgenic mice overexpressing interferon-alpha tissue specifically in thyrocytes. Interferon-alpha treatment of cultured PCCL3 rat thyrocytes increased markers of thyroid differentiation, levels of MHC class I, and expression of heat shock protein and CXCL10. This was associated with markedly increased nonapoptotic thyroid cell death. Consistent with these in vitro findings, transgenic mice overexpressing interferon-alpha in the thyroid displayed striking thyroid cell death characteristic of nonimmune thyroid destruction that progressed to profound primary hypothyroidism. Moreover, genes linked to cell death pathways, granzyme B, or known to be associated with recruitment of a cytotoxic immune response, CXCL10, interleukin-23, and TRIM21 were increased in the transgenic thyroids. Taken together, the etiology of interferon-induced thyroiditis likely involves both a direct toxic action on thyrocytes, as well as provocation of a destructive immune response.
2011-11-03 | GSE25115 | GEO
Project description:The thyroid gland is responsible for supplying the thyroid hormones to the body. The gland is an endocrine organ with an intricate structure enabling production, storage and release of the thyroid hormones. The gland is composed of numerous spherical follicles of varying sizes, surrounded by thyroid follicular epithelial cells, or thyrocytes. The thyrocytes surrounding the follicles generate the thyroid hormones in a multi-step process. Though the machinery responsible for the production of thyroid hormones by thyrocytes is well established, it remains unknown if all the thyrocytes resident in the thyroid gland are equally capable of generating thyroid hormones. In other words, the extent of molecular homogeneity between individual thyrocytes has not yet been investigated. To obtain an unbiased picture into the molecular heterogeneity present in zebrafish thyrocytes, we performed droplet based next-generation sequencing of individual thyrod gland cells. Using unsupervised clustering, we could identify all the major cell types present in the thyroid gland. Moreover, we could define sub-populations within the major cell-types, demonstrating the presence of molecular heterogeneity within nominally homogenous cell-populations.
2019-12-31 | GSE133466 | GEO
Project description:Radiation is an established cause of thyroid cancer and growing evidence supports a role for H2O2 in spontaneous thyroid carcinogenesis. Little is known about the molecular programs activated by these agents in thyroid cells. We profiled the DNA damage response and cell death induced by M-NM-3-radiation (0.1M-bM-^@M-^S5Gy) and H2O2 (0.0025M-bM-^@M-^S0.3mM) in primary human thyroid cells and T-cells. While the two cell types had more comparable radiation responses, 3- to 10-fold more H2O2 was needed to induce detectable DNA damage in thyrocytes. At H2O2 and radiation doses incurring double-strand breaks (DSB), cell death occurred after 24hrs in T-cells, but not in thyrocytes. We next prepared thyroid and T-cells primary cultures from 8 donors operated for non-cancerous pathologies and profiled their genome-wide transcriptional response 4hr after: 1) exposure to 1 Gy radiation, 2) treatment with H2O2, or 3) no treatment. Two H2O2 doses were investigated, calibrated in each cell type as to elicit levels of single- and double-strand breaks equivalent to 1 Gy M-NM-3-radiation. The transcriptional responses of thyrocyte and T-cells to radiation were similar, involving DNA repair and cell death genes. In addition to this transcriptional program, H2O2 also upregulated antioxidant genes in thyrocytes, including glutathione peroxidases (GPx) at the DSB-inducing dose. By contrast, a transcriptional storm involving thousands of genes was raised in T-cells. Finally, we showed that GPx inhibition reduced the DNA damaging effect of H2O2 in thyrocytes. We conjecture that defects of anti- H2O2 protection could promote spontaneous thyroid cancers. Here we characterize the response of thyrocytes to H2O2 from the perspective of DNA damage (SSB and DSB), cell death and genome-wide transcription. We adopted a dual comparative set up. First, in order to gain preliminary insights about which effects are specific to thyrocytes, all experiments were run in parallel in T-cells. Second, all experiments were replicated with radiation, providing a comparison with a proven etiological agent of PTCs. Hence, we investigated all 4 combinations of two factors: thyrocytes vs. T-cells and H2O2 vs. radiation. Cell lines divide indefinitively owning to basic dysfunctions of cell cycle controls. These have the potential to distort the stress response, DNA repair and cell death in particular. Hence, we worked exclusively on human primary cultures. The radiation and presumably also the H2O2 responses vary among individuals. We seek to average out individual effects by replicating the microarray experiments across the matched T-cells and thyrocytes of 8 donors.
2013-05-03 | E-GEOD-39156 | biostudies-arrayexpress
Project description:The CD40 gene, an important immune regulatory gene, is also expressed and functional on non-myeloid derived cells, many of which are targets for tissue specific autoimmune diseases, including d thyroid follicular cells in Graves’ disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. Here we show for the first time, that target-tissue over-expression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 over-expression augmented the production of thyroid specific antibodies, resulting in more severe experimental autoimmune Graves’ disease (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 over-expression, and showed decreased levels of TSHR stimulating antibodies and frequency of disease. We conclude that target tissue over-expression of CD40 plays a key role in the etiology of organ specific autoimmune disease. CD40 in Thyroid Autoimmunity: 1) Incubation of human thyroid cells with G28.5, a CD40 stimulating antibody, and purification of RNA, conversion to cDNA, measurement of mRNA expression using RNAseq. 2) Removal of thyroid tissues from CD40 over-expressing transgenic mice and wild type mice, purification of RNA, conversion to cDNA measurement of mRNA expression using RNAseq.
2012-10-03 | E-GEOD-39081 | biostudies-arrayexpress
Project description:The pathogenesis of thyroid dysgenesis (TD) is not well understood. Here, using a combination of single-cell RNA and spatial transcriptome sequencing, we identify a subgroup of NF-κB-activated thyrocytes located at the center of thyroid tissues in postnatal mice, which maintained a partially mesenchymal phenotype. These cells actively protruded out of the thyroid primordium and generated new follicles in zebrafish embryos through continuous tracing. Suppressing NF-κB signaling affected thyrocyte migration and follicle formation, leading to a TD-like phenotype in both mice and zebrafish. Interestingly, during thyroid folliculogenesis, myeloid cells played a crucial role in promoting thyrocyte migration by maintaining close contact and secreting TNF-α. We found that cebpa mutant zebrafish, in which all myeloid cells were depleted, exhibited thyrocyte migration defects. Taken together, our results suggest that myeloid-derived TNF-α-induced NF-κB activation plays a critical role in promoting the migration of vertebrate thyrocytes for follicle generation.
2023-11-16 | GSE231953 | GEO
Project description:The pathogenesis of thyroid dysgenesis (TD) is not well understood. Here, using a combination of single-cell RNA and spatial transcriptome sequencing, we identify a subgroup of NF-κB-activated thyrocytes located at the center of thyroid tissues in postnatal mice, which maintained a partially mesenchymal phenotype. These cells actively protruded out of the thyroid primordium and generated new follicles in zebrafish embryos through continuous tracing. Suppressing NF-κB signaling affected thyrocyte migration and follicle formation, leading to a TD-like phenotype in both mice and zebrafish. Interestingly, during thyroid folliculogenesis, myeloid cells played a crucial role in promoting thyrocyte migration by maintaining close contact and secreting TNF-α. We found that cebpa mutant zebrafish, in which all myeloid cells were depleted, exhibited thyrocyte migration defects. Taken together, our results suggest that myeloid-derived TNF-α-induced NF-κB activation plays a critical role in promoting the migration of vertebrate thyrocytes for follicle generation.
2023-11-16 | GSE231952 | GEO
Project description:To obtain a PTC cell model, primary human thyrocytes have been infected with a retrovirus expressing RET/PTC1 oncogene, using parental thyrocytes as control. The obtained RET/PTC-dependent differential miRNA expression profile, representing the effects of RET/PTC1 oncogene present in about one third of papillary thyroid carcinoma (PTC), models the early event of thyrocytes transformation ending to PTC.
2014-06-30 | GSE49400 | GEO