Department of Ophthalmology and Visual Neurosciences, University of Minnesota, Minneapolis, MN 55455, USA.
Stem Cell Institute, University of Minnesota, Minneapolis, MN 55455, USA.
Cells. 2021 Apr 2;10(4):789. doi: 10.3390/cells10040789.
Age-related macular degeneration (AMD), the leading cause of vision loss in the elderly, is characterized by loss of the retinal pigment epithelium (RPE). While the disease mechanism remains unclear, prior studies have linked AMD with RPE mitochondrial defects and genetic polymorphisms in the complement pathway. This study used RPE generated from induced pluripotent stem cells (iPSC-RPE), which were derived from human donors with or without AMD and genotyped for the complement factor H (CFH) AMD high-risk allele (rs1061170, Y402H) to investigate whether donor disease state or genotype had a detrimental effect on mitochondrial function and inflammation. Results show that cells derived from donors with AMD display decreased mitochondrial function under conditions of stress and elevated expression of inflammatory markers compared to iPSC-RPE from individuals without AMD. A more pronounced reduction in mitochondrial function and increased inflammatory markers was observed in CFH high-risk cells, irrespective of disease state. These results provide evidence for a previously unrecognized link between CFH and mitochondrial function that could contribute to RPE loss in AMD patients harboring the CFH high-risk genotype.
年龄相关性黄斑变性（AMD）是老年人视力丧失的主要原因，其特征是视网膜色素上皮（RPE）的丧失。虽然疾病机制尚不清楚，但先前的研究将 AMD 与 RPE 线粒体缺陷和补体途径的遗传多态性联系起来。本研究使用诱导多能干细胞（iPSC-RPE）产生的 RPE，这些细胞来自携带或不携带 AMD 的人类供体，并对补体因子 H（CFH）AMD 高风险等位基因（rs1061170，Y402H）进行基因分型，以研究供体疾病状态或基因型是否对线粒体功能和炎症有不利影响。结果表明，与不携带 AMD 的个体的 iPSC-RPE 相比，来自 AMD 供体的细胞在应激条件下表现出较低的线粒体功能和较高的炎症标志物表达。在 CFH 高风险细胞中，无论疾病状态如何，线粒体功能的降低和炎症标志物的增加更为明显。这些结果为 CFH 与线粒体功能之间以前未被认识到的联系提供了证据，这可能导致携带 CFH 高风险基因型的 AMD 患者的 RPE 丧失。
