Actions of insulin and vitamin A on Sertoli cells.
Ontology highlight
ABSTRACT:
SUBMITTER: Karl AF
PROVIDER: S-EPMC1161741 | biostudies-other | 1980 Mar
REPOSITORIES: biostudies-other
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Project description:Pituitary hormones can use local signaling molecules to regulate target tissue functions. In adult zebrafish testes, follicle-stimulating hormone (Fsh) strongly increases the production of insulin-like 3 (Insl3), a Leydig cell-derived growth factor found in all vertebrates. Little information is available regarding Insl3 function in adult spermatogenesis. The Insl3 receptors Rxfp2a and 2b were expressed by type A spermatogonia and Sertoli and myoid cells, respectively, in zebrafish testis tissue. Loss of insl3 increased germ cell apoptosis in males starting at 9 months of age, but spermatogenesis appeared normal in fully fertile, younger adults. Insl3 changed the expression of 409 testicular genes. Among others, retinoic acid (RA) signaling was up- and peroxisome proliferator-activated receptor gamma (Pparg) signaling was down-regulated. Follow-up studies showed that RA and Pparg signaling mediated Insl3 effects, resulting in the increased production of differentiating spermatogonia. This suggests that Insl3 recruits two locally active nuclear receptor pathways to implement pituitary (Fsh) stimulation of spermatogenesis.
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Project description:Long-term survival of allo- and xenotransplanted immune-privileged Sertoli cells (SCs) is well documented suggesting that SCs can be used to deliver foreign proteins for cell-based gene therapy. The aim of this study was to use a lentivirus carrying proinsulin cDNA to achieve stable expression and lowering of blood glucose levels (BGLs). A SC line transduced with the lentivirus (MSC-LV-mI) maintained stable insulin expression in vitro. These MSC-LV-mI cells were transplanted and grafts were analyzed for cell survival, continued proinsulin mRNA, and insulin protein expression. All grafts contained MSC-LV-mI cells that expressed proinsulin mRNA and insulin protein. Transplantation of MSC-LV-mI cells into diabetic mice significantly lowered BGLs for 4 days after transplantation. Interestingly, in three transplanted SCID mice and one transplanted BALB/c mouse, the BGLs again significantly lowered by day 50 and 70, respectively. This is the first time SC transduced with a lentiviral vector was able to stably express insulin and lower BGLs. In conclusion, a SC line can be modified to stably express therapeutic proteins (e.g., insulin), thus taking us one step further in the use of SCs as an immune-privileged vehicle for cell-based gene therapy.
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Project description:OBJECTIVE:Pancreatic β-cell mass and function are critical in glucose homeostasis. Their regulatory mechanisms have been studied principally under experimental conditions of reduced β-cell numbers, such as β-cell ablation and partial pancreatectomy. In the present study, we generated an opposite mouse model with an excessive amount of ectopic β-cells, and analyzed its consequence on β-cell mass and survival. METHODS:Mice underwent sub-renal transplantation (SRT) of pseudo-islets generated from a pancreatic β-cell line MIN6 or intra-pancreatic transplantation (IPT) of MIN6 cells, and morphological and functional changes of their endocrine pancreata were analyzed. Cellular fate of pancreatic β-cells after transplantation was traced using RipCre:Rosa26-tdTomato mice. By using MIN6 cells, we evaluated the roles of extracellular glucose, membrane potential, and insulin signaling on β-cell survival. RESULTS:SRT mice developed severe, progressive hypoglycemia associated with marked reduction in insulin-positive (Ins+) cell mass and apparent increase in apoptotic Ins+ cells. In in vitro experiments of MIN6 cells, insulin signaling blockade potently induced cell death, suggesting that local insulin action is required for β-cell survival. In fact, IPT (i.e. transplantation close to endogenous β-cells) resulted in fewer apoptotic Ins+ cells compared with those induced by SRT. On the other hand, β-cell mass was decreased in proportion to the decrease in blood glucose levels in both SRT and IPT mice, suggesting a contribution of hypoglycemia induced by systemic hyperinsulinemia. CONCLUSION:Insulin plays distinct roles in β-cell survival and β-cell mass regulation through its local and systemic actions on β-cells, respectively.
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Project description:Testis tissue was incubated under basal conditions for 2 days to allow for the assumed decrease of endogenous Insl3 production, then added exogenous, recombinant zebrafish Insl3 peptide (100 ng/mL) and continued the incubation for another 2 days, before collecting the tissue for analysis of gene expression
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Project description:The synthesis of prostanoids by the Sertoli cell was assessed as part of a study on the role of vitamin E in maintaining spermatogenesis. Analyses of eicosanoid synthesis from endogenous substrate were carried out using freshly isolated Sertoli-cell-enriched preparations from both pre-pubertal and adult rats fed purified diets with and without vitamin E, as well as cells carried in primary culture. Freshly isolated cells from both the immature and fully differentiated adult testes produced PGI2 (prostaglandin I2) and PGE2, but PGF2 alpha was produced only by cells of the adult vitamin E-deficient rat. Cells from adult controls synthesized PGF2 alpha after primary culture. In contrast with other hormone responses of this cell, which are refractory in the adult, FSH (follitropin) potentiated prostaglandin production by freshly isolated cells of both immature and adult rats. The FSH response of Sertoli cells from immature animals did not change after primary culture. Adult cells were refractory to the hormone after culture, but the total amounts of prostaglandins produced by these cells were 10-fold higher than by either freshly isolated or cells of the immature in culture. Analogues of cyclic AMP did not potentiate prostaglandin synthesis. However, mepacrine, a phospholipase inhibitor, blocked the FSH effect. The finding that Sertoli cells synthesize prostaglandins and FSH enhances prostaglandin production implicates a potential role for eicosanoids in spermatogenesis and suggests that vitamin E may affect intratesticular regulators.
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Project description:Mitochondria form filamentous networks that undergo continuous fission/fusion. In the pancreatic beta-cells, mitochondria are essential for the transduction of signals linking nutrient metabolism to insulin granule exocytosis. Here we have studied mitochondrial networks in the insulinoma cell line INS-1E, primary rat and human beta-cells. We have further investigated the impact of mitochondrial fission/fusion on metabolism-secretion coupling in INS-1E cells. Overexpression of hFis1 caused dramatic mitochondrial fragmentation, whereas Mfn1 evoked hyperfusion and the aggregation of mitochondria. Cells overexpressing hFis1 or Mfn1 showed reduced mitochondrial volume, lowered cellular ATP levels, and as a consequence, impaired glucose-stimulated insulin secretion. Decreased mitochondrial ATP generation was partially compensated for by enhanced glycolysis as indicated by increased lactate production in these cells. Dominant-negative Mfn1 elicited mitochondrial shortening and fragmentation of INS-1E cell mitochondria, similar to hFis1. However, the mitochondrial volume, cytosolic ATP levels, and glucose-stimulated insulin secretion were little affected. We conclude that mitochondrial fragmentation per se does not impair metabolism-secretion coupling. Through their impact on mitochondrial bioenergetics and distribution, hFis1 and Mfn1 activities influence mitochondrial signal generation thereby insulin exocytosis.
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Project description:Vitamin C (ascorbic acid, AA), as essential micro-nutrient and antioxidant, can affect multiple cellular processes. Previously, we showed that Vitamin C supplement could promote the proliferation and suppress apoptosis of porcine Sertoli cells, via modulating the global nucleic acid methylation levels to alter transcriptome and proteomics. Due to the differences between pig and rodent species, here we investigated the effects of Vitamin C on mouse TM4 Sertoli cells. Vitamin C (250µM) treatment of mouse TM4 Sertoli cells for 36h could significantly increase cell viability, promote cell proliferation and decrease the cell percentage with early apoptosis. Vitamin C (250µM, 36h) also significantly decreased ROS level, elevated mitochondrial function, altered the levels of nucleic acid N6-methylation (m6A) and modified the levels of histone H3 trimethylation (H3K4me3, H3K9Me3 and H3K36me3) of mouse TM4 Sertoli cells. Vitamin C (250µM, 36h) promoted the secretion of anti-müllerian hormone and Estrodiol, but decreased lactate metabolite in mouse TM4 Sertoli cells. RNA-seq identified 112 differentially expressed genes (DEGs) (74 up- and 38 down-regulated) (P≤0.05, |log2Fold Change|≥1) as induced by Vitamin C in mouse TM4 Sertoli cells. Gene enrichment analysis found multiple significantly enriched biological terms or pathways, including GO terms of regulation of response to biotic stimulus, homeostasis of number of cells, positive regulation of tumor necrosis factor production, GTPase activity, calmodulin binding etc., and KEGG signal pathways of calcium signal pathway, cGMP-PKG signaling pathway, steroid biosynthesis, arginine biosynthesis etc. 9 DEGs were selected for RT-qPCR validation and 8 of them showed the change trend consistent to RNA-seq. Taken together, Vitamin C (250µM, 36h) could modulate the functions of mouse TM4 Sertoli cells, through modifying the transcriptome to affect multiple signal pathways.
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