Thyrocyte Proliferation Research Articles

Defining the In Vivo Role of mTORC1 in Thyrocytes by Studying the TSC2 Conditional Knockout Mouse Model.

Background: The thyroid gland is susceptible to abnormal epithelial cell growth, often resulting in thyroid dysfunction. The serine-threonine protein kinase mechanistic target of rapamycin (mTOR) regulates cellular metabolism, proliferation, and growth through two different protein complexes, mTORC1 and mTORC2. The PI3K-Akt-mTORC1 pathway's overactivity is well associated with heightened aggressiveness in thyroid cancer, but recent studies indicate the involvement of mTORC2 as well. Methods: To elucidate mTORC1's role in thyrocytes, we developed a novel mouse model with mTORC1 gain of function in thyrocytes by deleting tuberous sclerosis complex 2 (TSC2), an intracellular inhibitor of mTORC1. Results: The resulting TPO-TSC2KO mice exhibited a 70-80% reduction in TSC2 levels, leading to a sixfold increase in mTORC1 activity. Thyroid glands of both male and female TPO-TSC2KO mice displayed rapid enlargement and continued growth throughout life, with larger follicles and increased colloid and epithelium areas. We observed elevated thyrocyte proliferation as indicated by Ki67 staining and elevated cyclin D3 expression in the TPO-TSC2KO mice. mTORC1 activation resulted in a progressive downregulation of key genes involved in thyroid hormone biosynthesis, including thyroglobulin (Tg), thyroid peroxidase (Tpo), and sodium-iodide symporter (Nis), while Tff1, Pax8, and Mct8 mRNA levels remained unaffected. NIS protein expression was also diminished in TPO-TSC2KO mice. Treatment with the mTORC1 inhibitor rapamycin prevented thyroid mass expansion and restored the gene expression alterations in TPO-TSC2KO mice. Although total thyroxine (T4), total triiodothyronine (T3), and TSH plasma levels were normal at 2 months of age, a slight decrease in T4 and an increase in TSH levels were observed at 6 and 12 months of age while T3 remained similar in TPO-TSC2KO compared with littermate control mice. Conclusions: Our thyrocyte-specific mouse model reveals that mTORC1 activation inhibits thyroid hormone (TH) biosynthesis, suppresses thyrocyte gene expression, and promotes growth and proliferation.

Cases of folliculogenesis in the rat's thyroid gland in norm and under experimental conditions

Objective: identification and characterization of the stages of formation of new follicles, as well as the frequency of folliculogenesis in various parts of the thyroid gland in the norm and in the experiment. Material and methods. The experiment was carried out on 36 mature white rats divided into three groups: control (I), 60-day exposure to sodium benzoate at a dose of 1000 mg/kg (II) and administration of mexidol at a dose of 50 mg/kg against the background of 60-day administration sodium benzoate (III). The stages of folliculogenesis were studied using light microscopy followed by a statistical analysis of its frequency. Results. The formation of a new follicle begins with the proliferation of thyrocytes on the wall of the mature follicle, after which a cavity is formed between the cells, into which they begin to secrete the colloid. In the process of follicle growth, the height of thyrocytes decreases, and the size of its cavity and the amount of colloid increase. In group II, signs of folliculogenesis were detected in the center of the organ by 1,7 and 1,4 times, and on the periphery — by 2 and 1,2 times less than in group I, and in group III — by 1,3 and 1,6 times more often in the center and 1,3 and 1,3 times in the periphery, compared with group II on the days 3 and 24 of the experiment. Conclusion. In the process of folliculogenesis in the thyroid gland, focal proliferation of thyrocytes develops in the wall of one of the follicles with further formation of the cavity of the newly formed follicle and its growth. In norm the frequency of new follicles formation is higher in the centre of the organ than in the periphery and decreases in both zones in the group of rats with sodium benzoate administration. In the group of rats where sodium benzoate administration was corrected by mexidol administration, the number of cases with the formation of young follicles increased, but the indicators did not reach the control figures.

Morphogenesis of thyropathies according to expression Oct3/4, PHH3, CK8, CK18 in chronic endogenous intoxication

Regeneration of internal organs under conditions of negative environmental impact, as well as adaptation to changing conditions of internal homeostasis in conditions of illness, is an urgent problem in regenerative medicine. The key links in the regulation of homeostasis are neuro-immune-endocrine relationships, where the main role in the regulation of metabolism is assigned to the thyroid gland. Morphological changes in the thyroid parenchyma under conditions of altered homeostasis in chronic endogenous intoxication (CEI) can lead to the formation of undiagnosed thyroid disorders and are not taken into the development of thanatogenesis. We conducted an IHC study to determine the main patterns of development of regenerative and adaptive processes of thyrocytes in conditions of CEI based on the expression of thyrocyte proliferation factors (PHH3), stem cells (Oct3/4), as well as to determine the risk of developing malignant neoplasms (CK8, CK18). It was found that in the formation of nodular neoplasms with a pronounced expression of PHH3 with a mitotic index of more than 25 %, it is necessary to conduct an IHC study to determine the expression of CK8, CK18 to identify the risk of developing thyroid neoplasms.

Late Breaking Abstracts

Late Breaking Abstracts

Maintaining the thyroid gland in mutant thyroglobulin–induced hypothyroidism requires thyroid cell proliferation that must continue in adulthood

Congenital hypothyroidism with biallelic thyroglobulin (Tg protein, encoded by the TG gene) mutation is an endoplasmic reticulum (ER) storage disease. Many patients (and animal models) grow an enlarged thyroid (goiter), yet some do not. In adulthood, hypothyroid TGcog/cog mice (bearing a Tg-L2263P mutation) exhibit a large goiter, whereas adult WIC rats bearing the TGrdw/rdw mutation (Tg-G2298R) exhibit a hypoplastic thyroid. Homozygous TG mutation has been linked to thyroid cell death, and cytotoxicity of the Tg-G2298R protein was previously thought to explain the lack of goiter in WIC-TGrdw/rdw rats. However, recent studies revealed that TGcog/cog mice also exhibit widespread ER stress–mediated thyrocyte death, yet under continuous feedback stimulation, thyroid cells proliferate in excess of their demise. Here, to examine the relative proteotoxicity of the Tg-G2298R protein, we have used CRISPR–CRISPR-associated protein 9 technology to generate homozygous TGrdw/rdw knock-in mice in a strain background identical to that of TGcog/cog mice. TGrdw/rdw mice exhibit similar phenotypes of defective Tg protein folding, thyroid histological abnormalities, hypothyroidism, and growth retardation. TGrdw/rdw mice do not show evidence of greater ER stress response or stress-mediated cell death than TGcog/cog mice, and both mouse models exhibit sustained thyrocyte proliferation, with comparable goiter growth. In contrast, in WIC-TGrdw/rdw rats, as a function of aging, the thyrocyte proliferation rate declines precipitously. We conclude that the mutant Tg-G2298R protein is not intrinsically more proteotoxic than Tg-L2263P; rather, aging-dependent difference in maintenance of cell proliferation is the limiting factor, which accounts for the absence of goiter in adult WIC-TGrdw/rdw rats.

Covid Vaccine as a Trigger for Grave’s Hyperthyroidism: Cases and Literature Review

Objective: Grave’s Disease is a systemic autoimmune disease directly caused by circulating auto-antibodies that bind to the thyrotropin receptor, subsequently inducing the production and release of thyroid hormone, proliferation of thyrocytes, and enlargement of the thyroid gland. Clinical practice has shown possible uncovering of Grave’s Disease following SARS-Cov-2 vaccine. The aim of this report is to shed the light on Grave’s Disease cases post SARS-Cov-2 vaccine, while reviewing the link between the vaccine and subsequent trigger of thyroid autoimmune hyperactivity. Cases: We present the case of a middle-aged woman with Grave’s disease following Hashimoto hypothyroidism manifesting 1 month post vaccine. A 36-year-old man presents with asymptomatic Grave’s disease 1 week following the vaccine. A 33-year-old woman presents with full blown Grave’s disease 9 days following vaccination. A 33-year-old man develops symptomatic Grave’s disease 3 weeks after the vaccine. Review: Cases presented above reflect different presentations of Grave’s disease. Moreso, the literature harbors similar cases of Grave’s disease recurrence, initial manifestation and exacerbation following SARS-Cov-2 vaccine. Grave’s disease etiology is autoimmune but environmental, genetic, and immunological factors contribute to its onset. The vaccine can potentially trigger autoimmune hyper-reactivity through the hyper-inflammatory response to the virus itself but also through the adjuvant found in the vaccine (Shoenfeld’s Syndrome) Conclusion: Cases of Grave’s disease manifestation or exacerbation post SARS-Cov-2 vaccines are reported. Theories are like SARS- Cov-2 -induced Grave’s Disease but also other mechanisms are uniquely mediated by vaccines. That vaccination benefit outweighs the potential risks but one should have a low threshold to test and follow patients at risk for auto-immune thyroid diseases after receiving SARS-CovV-2 vaccine.

Features of the expression of Fox-1 in rat’s thyroid after prenatal dexamethasone action

The purpose of the work was to establish the features of Fox-1 expression and distribution in the parenchyma of the thyroid gland of rats in the postnatal period of ontogeny in the norm and after intrauterine action of dexamethasone.Material and methods: thyroid gland of rats (162 animals) of the Wistar line at the age from 1 to 14 days of postnatal development. Experimentally, the animals were injected intrauterinely with a solution of dexamethasone at a dose of 0.05 ml at a dilution of 1:40 on the 18th day of the dated pregnancy. The material was examined using a set of methods of morphological studies (production of histological serial sections, survey microscopy, morphometry, immunohistochemistry and statistical processing).Results of the research. In the thyroid glands of neonatal prenatal dexamethasone, the parenchyma was well developed and consisted of hollow colloid-type follicles and single colloid-type microfollicles, and a bright cytoplasmic reaction with Fox-1 antibodies was observed throughout the organ parenchyma. In the thyroid glands of animals of the 3rd day of life, morphological changes occurred in all groups of the experiment. In animals of the experimental group, hollow follicles of colloidal type of small, medium and large diameter were chaotically visualized throughout the body, and large follicles of irregular shape with immunohistochemical weak or negative reaction with Fox-1 antibodies in thyrocytes and lumen without colloidal evidence, which detected a decrease in the specific synthetic activity in these thyrocytes. On day 7 in the experimental group in the flattened thyrocytes of overstretched follicles, the expression of Fox-1 was present only in the apical part. On days 11-14 of postnatal development in the thyroid glands of rats experimentally prenatally exposed to dexamethasone in the wall of large follicles with flattened epithelium began extrafollicular proliferation of thyrocytes on the background of visualization in the lumen of these follicles desquamated cells. Intensive perinuclear and cytoplasmic Fox-1 positive reaction was present in extrafollicular proliferating thyrocytes.Conclusions. 1. The detected changes in the first day of life in the thyroid gland of rats indicated that prenatal administration of dexamethasone affects the intensification of differentiation not only structural and functional units - follicles, but also a specific synthetic intracellular apparatus of thyrocytes, judging by the intensification of Fox-1. Thus, immature pre-mRNA is converted into mature mRNA, from which thyroid proteins, in particular thyroglobulin, are translated. By the time of birth, this process in the experimental group reaches a significant development, covering the entire parenchyma of the gland. 2. In rats prenatally receiving dexamethasone, the period of lactation was characterized by intense structural changes in the thyroid gland, in particular intracellularly in thyrocytes of monolayer flattened epithelium, the expression of Fox-1 antibodies was sharply reduced, which was then replaced by a bright cytoplasmic reaction in proliferative clusters and follicles of colloidal type of secretion, which is an adaptive-compensatory mechanism of intracellular enhancement of proliferation of synthesizing organelles in response to the restructuring of a significant number of existing follicles by hypofunctional type, aimed at maintaining normal levels of thyroid function.

Electron-microscopic features of changes in the adrenal and thyroid glands in chronic hypoxia

The aimof the studywas to study the characteristic features of ultrastructural changes in the cellular and extracellular matrix of the adrenal and thyroid glands in chronic hypoxia.Materials and methods.The study used the thyroid and adrenal glands of healthy adult male white rats weighing 180-200 g. The anatomical, histological, histochemical, electron microscopic and morphometric methods were used.Results.We found that the response of thyroid and adrenal cells to hypoxia is different. So, since the processes of proliferation in the cells of the thyroid gland occur faster and earlier, all tissues are restored on the 15th day of the experiment in the thyroid gland, and in the adrenal gland are restored only on the 30th day of the experiment. And this can be regarded as a higher degree of sensitivity of the adrenal glands to hypoxia, which is a stronger stress factor than the thyroid gland.Summary.The structures of the thyroid gland adapt to long-term hypoxia earlier, and responds to this with ultrastructural rearrangement – hyperplasia, hypertrophy and proliferation of thyrocytes.

Late Breaking Abstracts

Late Breaking Abstracts

The Amino Acid Transporter Mct10/Tat1 Is Important to Maintain the TSH Receptor at Its Canonical Basolateral Localization and Assures Regular Turnover of Thyroid Follicle Cells in Male Mice.

Cathepsin K-mediated thyroglobulin proteolysis contributes to thyroid hormone (TH) liberation, while TH transporters like Mct8 and Mct10 ensure TH release from thyroid follicles into the blood circulation. Thus, thyroid stimulating hormone (TSH) released upon TH demand binds to TSH receptors of thyrocytes, where it triggers Gαq-mediated short-term effects like cathepsin-mediated thyroglobulin utilization, and Gαs-mediated long-term signaling responses like thyroglobulin biosynthesis and thyrocyte proliferation. As reported recently, mice lacking Mct8 and Mct10 on a cathepsin K-deficient background exhibit excessive thyroglobulin proteolysis hinting towards altered TSH receptor signaling. Indeed, a combination of canonical basolateral and non-canonical vesicular TSH receptor localization was observed in Ctsk−/−/Mct8−/y/Mct10−/− mice, which implies prolonged Gαs-mediated signaling since endo-lysosomal down-regulation of the TSH receptor was not detected. Inspection of single knockout genotypes revealed that the TSH receptor localizes basolaterally in Ctsk−/− and Mct8−/y mice, whereas its localization is restricted to vesicles in Mct10−/− thyrocytes. The additional lack of cathepsin K reverses this effect, because Ctsk−/−/Mct10−/− mice display TSH receptors basolaterally, thereby indicating that cathepsin K and Mct10 contribute to TSH receptor homeostasis by maintaining its canonical localization in thyrocytes. Moreover, Mct10−/− mice displayed reduced numbers of dead thyrocytes, while their thyroid gland morphology was comparable to wild-type controls. In contrast, Mct8−/y, Mct8−/y/Mct10−/−, and Ctsk−/−/Mct8−/y/Mct10−/− mice showed enlarged thyroid follicles and increased cell death, indicating that Mct8 deficiency results in altered thyroid morphology. We conclude that vesicular TSH receptor localization does not result in different thyroid tissue architecture; however, Mct10 deficiency possibly modulates TSH receptor signaling for regulating thyrocyte survival.

A Gq Biased Small Molecule Active at the TSH Receptor.

G protein coupled receptors (GPCRs) can lead to G protein and non-G protein initiated signals. By virtue of its structural property, the TSH receptor (TSHR) has a unique ability to engage different G proteins making it highly amenable to selective signaling. In this study, we describe the identification and characterization of a novel small molecule agonist to the TSHR which induces primary engagement with Gαq/11. To identify allosteric modulators inducing selective signaling of the TSHR we used a transcriptional-based luciferase assay system with CHO-TSHR cells stably expressing response elements (CRE, NFAT, SRF, or SRE) that were capable of measuring signals emanating from the coupling of Gαs, Gαq/11, Gβγ, and Gα12/13, respectively. Using this system, TSH activated Gαs, Gαq/11, and Gα12/13 but not Gβγ. On screening a library of 50K molecules at 0.1,1.0 and 10 μM, we identified a novel Gq/11 agonist (named MSq1) which activated Gq/11 mediated NFAT-luciferase >4 fold above baseline and had an EC50= 8.3 × 10−9 M with only minor induction of Gαs and cAMP. Furthermore, MSq1 is chemically and structurally distinct from any of the previously reported TSHR agonist molecules. Docking studies using a TSHR transmembrane domain (TMD) model indicated that MSq1 had contact points on helices H1, H2, H3, and H7 in the hydrophobic pocket of the TMD and also with the extracellular loops. On co-treatment with TSH, MSq1 suppressed TSH-induced proliferation of thyrocytes in a dose-dependent manner but lacked the intrinsic ability to influence basal thyrocyte proliferation. This unexpected inhibitory property of MSq1 could be blocked in the presence of a PKC inhibitor resulting in derepressing TSH induced protein kinase A (PKA) signals and resulting in the induction of proliferation. Thus, the inhibitory effect of MSq1 on proliferation resided in its capacity to overtly activate protein kinase C (PKC) which in turn suppressed the proliferative signal induced by activation of the predomiant cAMP-PKA pathway of the TSHR. Treatment of rat thyroid cells (FRTL5) with MSq1 did not show any upregulation of gene expression of the key thyroid specific markers such as thyroglobulin(Tg), thyroid peroxidase (Tpo), sodium iodide symporter (Nis), and the TSH receptor (Tshr) further suggesting lack of involvement of MSq1 and Gαq/11 activation with cellular differentation. In summary, we identified and characterized a novel Gαq/11 agonist molecule acting at the TSHR and which showed a marked anti-proliferative ability. Hence, Gq biased activation of the TSHR is capable of ameliorating the proliferative signals from its orthosteric ligand and may offer a therapeutic option for thyroid growth modulation.

Identification of Transient Receptor Potential Channel 4-Associated Protein as a Novel Candidate Gene Causing Congenital Primary Hypothyroidism

Background: Congenital primary hypothyroidism (CH) is the most common endocrine disorder in neonates. Methods: To identify novel genes, we performed whole exome sequencing (WES) in 6 patients with CH due to thyroid dysgenesis (TD). The potential effects of the most relevant variants were analyzed using in silico prediction tools. The most promising candidate gene, transient receptor potential channel 4-associated protein (TRPC4AP), was sequenced in 179 further patients with TD. Expression of TRPC4AP in human thyroid was investigated using RT-PCR. Trpc4ap- functional analysis was performed in Xenopus laevis using Morpholino (MO) antisense oligomers. Results: WES identified a likely damaging mutation in TRPC4AP leading to a de novo stop codon p.Q552*. Targeted sequencing of TRPC4AP demonstrated gene variants with predicted damaging potential in 5 patients resulting each in an amino acid exchange (p.P706S, p.F729L, p.S777C, and p.N229S). We demonstrated that TRPC4AP is expressed in human thyroid gland tissue. Using Xenopus laevis, we showed that the volume of the tadpole thyroid anlage was reduced by 20% in Trpc4ap MO knockdowns compared to controls and by 41% in “Clustered Regularly Interspaced Short Palindromic Repeats”/Cas9-mediated gene knockout experiments. Discussion: A recognized interaction of TRPC4AP and the NF-kappa-B-essential-modulator encoded by IKBKG gene was identified by IPA analysis. IKBKG plays a role in activation of the NF-κB-signaling pathway and regulates genes involved in proliferation and survival of thyrocytes and expression of key enzymes of thyroid hormone synthesis. Conclusion: TRPC4AP was identified as a novel candidate gene in TD, but further studies are needed to validate its role in thyroid function.

The activity of proliferation and apoptosis of thyrocytes in the thyroid tissue of patients of nodular goiter with autoimmune thyroiditis considering the polymorphism of the BCL-2 (RS17759659), CTLA-4 (RS231775), APO-1/FAS (RS2234767) genes

Nodular goiter with autoimmune thyroiditis is one of the most important problems of modern endocrinology, with inadequately studied etiological and pathogenic mechanisms of development. It is characterized by the lack of objective and reliable diagnostic methods, effective treatment methods, uncertain therapy or indications for the choice of treatment methods. A total we have examined 125 patients who were operated for a nodular endemic goiter with autoimmune thyroiditis. Investigated the activity of proliferation and apoptosis of thyrocytes in the thyroid tissue of patients of nodular goiter with autoimmune thyroiditis considering the polymorphism of the bcl-2 (rs17759659), ctla-4 (rs231775), apo-1/fas (rs2234767) genes. The expression/density markers - Fas/ FasL, Bcl-2, p53 and Ki-67 on the thyrocytes in the lymphoid infiltration and destruction areas, as well as in normal thyroid tissue (as a control) were studied. The number of immunoreactive cells, which expressed the above-mentioned regulating apoptosis and proliferation markers in NGAIT patients, depending on the genes polymorphism BCL-2 (rs17759659), CTLA-4 (rs231775) and APO-1/Fas (rs2234767) were counted. It was found that in NGAIT patients a few links of programmable thyroid cell killing of Fas-induced apoptosis were activated, and associated with the polymorphic cite of BCL-2 (rs17759659) gene and almost 6 times weaker with CTLA-4 (rs231775) gene, through enhanced expression of Fas and Fas L on the cells surface in lymphoid infiltration and destruction areas (stronger in GG genotype carriers of BCL-2 gene).

Localization and characterization of thyroid microcalcifications: A histopathological study.

Thyroid calcification is frequent in thyroid nodules. The aim of our study was to evaluate the prevalence of calcifications in thyroid tissue samples of patients with various thyroid diseases, and to identify their composition according to their localization. Among 50 thyroid samples included, 56% were malignant (papillary carcinoma) and 44% were benign (adenoma, multinodular goiter, Graves’ disease, sarcoidosis). Calcifications were found in 95% of samples using polarised light microscopy, whereas only 12% were described in initial pathological reports. Three types were individualised and analyzed by infrared spectrometry (μFTIR): colloid calcifications composed of calcium oxalate, capsular calcifications and psammoma bodies, both composed of calcium phosphate. Of notice, psammoma bodies characterized by FE-SEM were composed of concentric structure suggesting a slow process for crystal deposition. Calcium phosphates were found only in malignant samples whereas calcium oxalate was not associated with a define pathology. Proliferation assessed by KI67 staining was high (33% of positive follicles), and RUNX2, OPN, and CD44 positive staining were detected in thyrocytes with a broad variation between samples. However, thyrocyte proliferation and differentiation markers were not associated with the number of crystals. TRPV5 and CaSR expression was also detected in thyrocytes. mRNA transcripts expression was confirmed in a subgroup of 10 patients, altogether with other calcium transporters such as PMCA1 or Cav1.3. Interestingly, TRPV5 mRNA expression was significantly associated with number of colloid calcifications (rho = -0.72; p = 0.02). The high prevalence of calcium oxalate crystals within colloid gel raises intriguing issues upon follicle physiology for calcium and oxalate transport.

A Toxicogenomic Approach Reveals a Novel Gene Regulatory Network Active in In Vitro and In Vivo Models of Thyroid Carcinogenesis.

Epidemiological and experimental studies emphasize the link between environmental chemicals exposure and thyroid cancer. However, this association is strongly debated and the mechanisms of action of environmental thyroid carcinogens still need to be identified. The analysis of in vitro transcriptomic data developed to investigate the effects of chlorpyrifos on immortalized thyrocytes highlighted the impaired expression of genes involved in endodermal carcinogenesis. This endodermal carcinogenic gene-network (ECGN, including Zfp36l2, Dmbt1, Ddit4), was validated in cellular and mouse models of thyroid carcinogenesis, characterized by the constitutive activation of the mitogen-activated protein kinase (MAPK) pathway and in immortalized thyrocytes exposed to tetrachlorodibenzo-p-dioxin (TCDD) and chlorpyrifos (CPF). The mRNA levels of Zfp36l2, Dmbt1 and Ddit4 were increased in models characterized by MAPK activation or following TCDD exposure, whereas they were inhibited by CPF exposure. Overall, the ECGN transcripts identify a novel gene-regulatory network associated with thyroid carcinogenesis promoted by genetic mutation or by environmental carcinogens. The latter have opposite effects on the modulation of the ECGN transcripts according to their mechanisms of action in promoting carcinogenesis. Therefore, the analyses of ECGN might be helpful in discriminating compounds that promote cellular survival associated or not to proliferation of thyrocytes.

LncRNA BCAR4 up-regulates EGFR and thus promotes human thyrocyte proliferation.

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Thyrocyte-specific deletion of insulin and IGF-1 receptors induces papillary thyroid carcinoma-like lesions through EGFR pathway activation.

Insulin and insulin-like growth factor (IGF)-1 signaling in the thyroid are thought to be permissive for the coordinated regulation by thyroid-stimulating hormone (TSH) of thyrocyte proliferation and hormone production. However, the integrated role of insulin receptor (IR) and IGF-1 receptor (IGF-1R) in thyroid development and function has not been explored. Here, we generated thyrocyte-specific IR and IGF-1R double knockout (DTIRKO) mice to precisely evaluate the coordinated functions of these receptors in the thyroid of neonates and adults. Neonatal DTIRKO mice displayed smaller thyroids, paralleling defective folliculogenesis associated with repression of the thyroid-specific transcription factor Foxe1. By contrast, at postnatal day 14, absence of IR and IGF-1R paradoxically induced thyrocyte proliferation, which was mediated by mTOR-dependent signaling pathways. Furthermore, we found elevated production of TSH during the development of follicular hyperplasia at 8 weeks of age. By 50 weeks, all DTIRKO mice developed papillary thyroid carcinoma (PTC)-like lesions that correlated with induction of the ErbB pathway. Taken together, these data define a critical role for IR and IGF-1R in neonatal thyroid folliculogenesis. They also reveal an important reciprocal relationship between IR/IGF-1R and TSH/ErbB signaling in the pathogenesis of thyroid follicular hyperplasia and, possibly, of papillary carcinoma.

Diosgenin inhibits cell proliferation of primary human thyrocytes via downregulation of PI3K/Akt signaling pathway

Purpose : To determine the potential influence of diosgenin on proliferation of human thyrocytes and its possible mechanism. Methods : Primary human thyrocytes were cultured and treated with diosgenin at various time intervals. Anti-proliferative activity was determined by MTT assay. Cell proliferation was evaluated by EdU assay while cell cycle was analyzed using fluorescence-activated cell sorting (FACS) method. Protein expression of p21 (CIP1), p27 (KIP1), cyclins, protein kinase B (Akt), phosphatidylinositol 3 kinase (PI3K) and p-Akt was determined by the western blot. Results : Diosgenin inhibited proliferation of primary human thyrocytes and caused G0/G1 arrest in a concentration-dependent manner. It also downregulated cyclin D1 and phosphorylation of PI3K and Akt, but upregulated p21 and p27. Conclusion : Inhibition of proliferation of primary human thyrocytes by diosgenin occurs via downregulation of PI3K/Akt signaling pathway. Therefore, diosgenin can be developed as a potential drug for the treatment of thyroid disease. Keywords : Diosgenin, Proliferation, Primary human thyrocytes, PI3K/Akt signaling pathway

Морфологічні особливості щитоподібної залози щурів із експериментальним аутоімунним тиреоїдитом після введення алогенних кріоконсервованих фетальних клітин

The designing of novel approaches and search for more efficient means to normalize the thyroid gland (TG) function in autoimmune thyroiditis (AIT) is a topical task in current endocrinology. Here we assessed the effect of cryopreserved allogeneic fetal liver cells (cFLCs) and those of fetal mesodermal tissues (cFMTCs) on thyroid gland (TG) morphostructure in rats with experimental AIT. The cFLCs and cFMTCs were demonstrated to positively affect the TG of rats with induced AIT even at the early stages of the study. Both types of fetal cells potentiated the thyrocyte proliferation and microfollicle differentiation even in 7 days after administration. This effect persisted during a month of observation. Herewith the cells of mesodermal origin had a more pronounced effect than the fetal liver ones. Our findings testify to the prospects of using stem and progenitor cells of fetal origin for AIT correction, that may be the basis in designing a novel efficient approach to the therapy of autoimmune damage of thyroid parenchyma.Probl Cryobiol Cryomed 2017; 27(4): 356-366

Commentary: Thyrotropin Stimulates Differentiation Not Proliferation of Normal Human Thyrocytes in Culture.

Commentary: Thyrotropin Stimulates Differentiation Not Proliferation of Normal Human Thyrocytes in Culture.