Department of Cell Biology, University of Oklahoma Health Sciences Center, 940 Stanton L. Young Blvd., BMSB 553, Oklahoma, OK 73104, USA.
Genes & Human Disease Research Program, Oklahoma Medical Research Foundation, Oklahoma, OK 73104, USA.
Int J Mol Sci. 2024 Jul 6;25(13):7435. doi: 10.3390/ijms25137435.
Thyroid hormone (TH) plays an essential role in cell proliferation, differentiation, and metabolism. Experimental and clinical studies have shown a potential association between TH signaling and retinal degeneration. The suppression of TH signaling protects cone photoreceptors in mouse models of retinal degeneration, whereas excessive TH signaling induces cone degeneration, manifested as reduced light response and a loss of cones. This work investigates the genes/transcriptomic alterations that might be involved in TH-induced cone degeneration in mice using single-cell RNA sequencing (scRNAseq) analysis. One-month-old C57BL/6 mice received triiodothyronine (T3, 20 µg/mL in drinking water) for 4 weeks as a model of hyperthyroidism/excessive TH signaling. At the end of the experiments, retinal cells were dissociated, and cell viability was analyzed before being subjected to scRNAseq. The resulting data were analyzed using the Seurat package and visualized using the Loupe browser. Among 155,866 single cells, we identified 14 cell clusters, representing various retinal cell types, with rod and cone clusters comprising 76% and 4.1% of the total cell population, respectively. Cone cluster transcriptomes demonstrated the most alterations after the T3 treatment, with 450 differentially expressed genes (DEGs), accounting for 38.5% of the total DEGs. Statistically significant changes in the expression of genes in the cone cluster revealed that phototransduction and oxidative phosphorylation were impaired after the T3 treatment, along with mitochondrial dysfunction. A pathway analysis also showed the activation of the sensory neuronal/photoreceptor stress pathways after the T3 treatment. Specifically, the eukaryotic initiation factor-2 signaling pathway and the cAMP response element-binding protein signaling pathway were upregulated. Thus, excessive TH signaling substantially affects cones at the transcriptomic level. The findings from this work provide an insight into how excessive TH signaling induces cone degeneration.
甲状腺激素（TH）在细胞增殖、分化和代谢中发挥着重要作用。实验和临床研究表明，TH 信号与视网膜变性之间存在潜在关联。抑制 TH 信号可保护视网膜变性的小鼠模型中的视锥细胞，而过多的 TH 信号则会诱导视锥细胞变性，表现为光反应减弱和视锥细胞丧失。本研究使用单细胞 RNA 测序（scRNAseq）分析，研究了可能参与 TH 诱导的小鼠视锥细胞变性的基因/转录组变化。将 1 个月大的 C57BL/6 小鼠用三碘甲状腺原氨酸（T3，饮用水中 20μg/ml）处理 4 周作为甲状腺功能亢进/TH 信号过度的模型。实验结束时，分离视网膜细胞，在进行 scRNAseq 之前分析细胞活力。使用 Seurat 包对所得数据进行分析，并使用 Loupe 浏览器进行可视化。在 155866 个单细胞中，我们鉴定出 14 个细胞簇，代表各种视网膜细胞类型，其中棒状和视锥细胞簇分别占总细胞群的 76%和 4.1%。T3 处理后，视锥细胞簇的转录组显示出最大的变化，有 450 个差异表达基因（DEGs），占总 DEGs 的 38.5%。对细胞簇中基因表达的统计显著变化表明，T3 处理后光转导和氧化磷酸化受损，同时线粒体功能障碍。通路分析还表明，T3 处理后感觉神经元/光感受器应激途径被激活。具体而言，真核起始因子 2 信号通路和 cAMP 反应元件结合蛋白信号通路被上调。因此，过多的 TH 信号在转录组水平上显著影响视锥细胞。本研究结果提供了一个深入了解过多的 TH 信号如何诱导视锥细胞变性的视角。
