Saini Janmeet S, Corneo Barbara, Miller Justine D, Kiehl Thomas R, Wang Qingjie, Boles Nathan C, Blenkinsop Timothy A, Stern Jeffrey H, Temple Sally
Neural Stem Cell Institute, Rensselaer, NY 12144, USA; Department of Biomedical Sciences, University at Albany - SUNY, Albany, NY 12201, USA.
Stem Cell Core Facility, Columbia University Medical Center, New York, NY 10032, USA.
Cell Stem Cell. 2017 May 4;20(5):635-647.e7. doi: 10.1016/j.stem.2016.12.015. Epub 2017 Jan 26.
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.
年龄相关性黄斑变性（AMD）会影响视网膜色素上皮（RPE），这是一种对光感受器存活至关重要的细胞单层，并且是老年人视力丧失的主要原因。对于干性AMD尚无改变疾病进程的疗法，干性AMD的特征是视网膜下玻璃膜疣沉积物的积累和补体驱动的炎症。我们报告了从已确诊AMD的患者中获得人诱导多能干细胞（hiPSC），包括两名具有罕见ARMS2/HTRA1纯合基因型的供体。hiPSC衍生的RPE细胞产生几种与AMD/玻璃膜疣相关的蛋白质，而来自AMD供体的细胞显示补体和炎症因子显著增加，这在ARMS2/HTRA1细胞系中最为明显。通过使用一组AMD生物标志物和候选药物筛选，并结合转录组分析，我们发现烟酰胺（NAM）通过抑制玻璃膜疣蛋白以及炎症和补体因子，同时上调核小体、核糖体和染色质修饰基因，改善了疾病相关表型。因此，靶向NAM调节的途径是开发对抗AMD疗法的一个有前景的途径。
