Single-cell RNA sequencing of zebrafish thyroid cells
Ontology highlight
ABSTRACT:
ORGANISM(S): Danio rerio
PROVIDER: GSE133466 | GEO | 2019/12/31
REPOSITORIES: GEO
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Project description:Amiodarone reversibly decreases sodium-iodide symporter mRNA expression at therapeutic concentrations and induces antioxidant responses at supraphysiological concentrations in cultured human thyroid follicles Amiodarone, a potent antiarrhythmic agent, is a highly active oxidant, exerting cytotoxic effects on thyrocytes at pharmacological concentrations. Patients receiving amiodarone usually remain euthyroid, but occasionally develop thyroid dysfunction, such as amiodarone-associated hypothyroidism or amiodarone-induced thyrotoxicosis. To elucidate the mechanism by which amiodarone elicits thyroid dysfunction, human thyroid follicles were cultured with TSH and amiodarone at therapeutic (1-2 microM) and pharmacological (10-20microM) concentrations, and the drug-induced effect on whole human gene expression was analyzed by cDNA microarray. Amiodarone at 1-2microM decreased the expression level of the sodium-iodide symporter (NIS) to nearly half, but did not affect genes participating in thyroid hormonogenesis (thyroid peroxidase, thyroglobulin, pendrin, NADPH oxidase). Higher concentrations (10-20 microM) decreased the expression of all these genes, accompanied by increased expression of antioxidant proteins such as heme oxygenase 1 and ferritin. When thyroid follicles obtained from a patient with Graves’ disease who had been treated with amiodarone for 2 months before thyroidectomy were cultured in amiodarone-free medium, TSH-induced thyroid function was intact, suggesting that amiodarone at a maintenance dose did not elicit any cytotoxic effect on thyrocytes. The ultrastructural features of cultured thyroid follicles were compatible with these in vitro findings. These in vitro and ex vivo findings suggest that patients taking maintenance doses of amiodarone usually remain euthyroid, probably due to escape from the Wolff-Chaikoff effect mediated by decreased expression of NIS mRNA. Furthermore, amiodarone is not cytotoxic for thyrocytes at therapeutic concentrations but elicits cytotoxicity through oxidant activity at supra-physiological concentrations. Keywords: Cultured human thyroid follicles
2008-07-19 | GSE12164 | GEO
Project description:Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of hTSH, we studied the effects of polyinosinic-polycytidylic acid (Poly(I:C)), a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-g, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose-dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis. This data was published in Endocrinology, vol.148, 3226-3235, 2007. Keywords: Cultured human thyroid follicles
2008-07-18 | GSE12154 | GEO
Project description:Although viral infection is thought to be associated with subacute thyroiditis and probably with autoimmune thyroid disease, possible changes in thyroid function during the prodromal period of infection or subclinical infection remain largely unknown. Recently, it was shown that pathogen-associated molecular patterns stimulate Toll-like receptors (TLR) and activate innate immune responses by producing type I interferons (IFN). Using a human thyroid follicle culture system, in which de novo synthesized thyroid hormones are released into the culture medium under physiological concentrations of hTSH, we studied the effects of polyinosinic-polycytidylic acid (Poly(I:C)), a chemical analog of viral double-stranded RNA (dsRNA), on TSH-induced thyroid function. Thyrocytes expressed ligands for dsRNA (TLR 3, CD14, and RIG-1) comparable to the TSH receptor. DNA microarray and real-time PCR analyses revealed that dsRNA increased the expression of mRNA for TLR3, IFN-g, interferon-regulating factors, proinflammatory cytokines, and class I MHC, whereas genes associated with thyroid hormonogenesis (NIS, peroxidase, deiodinases) were suppressed. In accordance to these data, Poly(I:C) suppressed TSH-induced 125I uptake and hormone synthesis dose-dependently, accompanied by a decrease in the ratio of 125I-T3/125I-T4 released into the culture medium, whereas peptidoglycan, lipopolysaccharides, or unmethylated CpG DNA, ligands for TLR2, TLR4, and TLR9, respectively, had no significant effect. These inhibitory effects of Poly(I:C) were not blocked by a neutralizing antibody against TLR3 and an anti-IFN alpha/beta receptor antibody. These in vitro findings suggest that when thyrocytes are infected with certain viruses, dsRNA formed intracellularly in thyrocytes may be a cause for thyroid dysfunction, leading to development of autoimmune thyroiditis. This data was published in Endocrinology, vol.148, 3226-3235, 2007. Experiment Overall Design: Two conditioned experimets, control vs. double-stranded RNA (polyI-C), cultured for 6
2008-10-21 | E-GEOD-12154 | 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.
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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: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).
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Project description:Thyroid follicular cells (TFCs) are responsible for generation, storage and release of thyroid hormone. Single-cell analysis of zebrafish thyroid gland demonstrated transcriptional heterogeneity within the TFC population (Gillotay et al., bioRxiv, 2020. doi: 10.1101/2020.01.13.891630. GEO dataset for single-cell RNA-Seq.: GSE133466). Particularly, TFC displayed transcriptional heterogeneity in the expression of pax2a, a transcription factor involved in differentiation and maturation of TFCs. To validate the genetic heterogeneity, we generated a pax2a knock-in line, in which mKO2 expression is driven by endogenous pax2a locus. Using Tg(tg:nls-EGFP); pax2a:mKO2-Knock-in, we sorted for TFCs (GFP+) and separated the pax2a-Low (mKO2-Low) and pax2a-High (mKO2-High) populations for NGS.
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Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.
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Project description:The function of the thyroid gland is to metabolize iodide to synthesize hormones that act on almost all tissues and are essential for normal growth and metabolism. Low plasma levels of thyroid hormones lead to hypothyroidism, which is one of the most common diseases in the general population and cannot be always satisfactorily treated by lifelong hormone replacement. Therefore, in addition to the lack of in vitro tractable models to study human thyroid development, differentiation and maturation, there is a need for new therapeutic approaches that involve replacement of thyroid tissue to better control hormone balance. Here we report the first model of thyroid organoids derived from human embryonic stem cells that produce thyroid hormones in vitro and are capable of restoring plasma thyroid hormone levels when transplanted into athyreotic mice.
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