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首页> 外文期刊>Cell stem cell >Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration
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Nicotinamide Ameliorates Disease Phenotypes in a Human iPSC Model of Age-Related Macular Degeneration

机译：烟酰胺在人体IPSC年龄相关性黄斑变性模型中改善疾病表型

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摘要

Age-related macular degeneration (AMD) affects the retinal pigment epithelium (RPE), a cell monolayer essential for photoreceptor survival, and is the leading cause of vision loss in the elderly. There are no disease-altering therapies for dry AMD, which is characterized by accumulation of subretinal drusen deposits and complement-driven inflammation. We report the derivation of human-induced pluripotent stem cells (hiPSCs) from patients with diagnosed AMD, including two donors with the rare ARMS2/HTRA1 homozygous genotype. The hiPSC-derived RPE cells produce several AMD/drusen-related proteins, and those from the AMD donors show significantly increased complement and inflammatory factors, which are most exaggerated in the ARMS2/HTRA1 lines. Using a panel of AMD biomarkers and candidate drug screening, combined with transcriptome analysis, we discover that nicotinamide (NAM) ameliorated disease-related phenotypes by inhibiting drusen proteins and inflammatory and complement factors while upregulating nucleosome, ribosome, and chromatin-modifying genes. Thus, targeting NAM-regulated pathways is a promising avenue for developing therapeutics to combat AMD.
机译：与年龄相关的黄斑变性（AMD）影响视网膜颜料上皮（RPE），一种用于感光体存活的细胞单层，是老年人视力丧失的主要原因。干燥AMD没有疾病改变的疗法，其特征在于沉积物玻璃淤积和补体驱动的炎症的积累。我们报告了从诊断患者患者的人诱导的多能干细胞（HIPSC）的衍生，其中包括两个带有稀有臂2 / HTRA1纯合学基因型的供体。 HIPSC衍生的RPE细胞产生几种AMD /玻璃玻璃相关蛋白质，并且来自AMD供体的蛋白显示出显着增加的补体和炎症因子，其在ARMS2 / HTRA1线中最夸张。使用AMD生物标志物和候选药物筛选面板，结合转录组分析，我们发现烟胺酰胺（NAM）通过抑制葡萄蛋白和炎症和补体因子而有效的疾病相关表型，同时上调核细胞体，核糖体和染色质改性基因。因此，针对NAM调节的途径是开发治疗方法的承诺大道。

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