Epithelial to mesenchymal transition (EMT) is a biological process involved in tissue morphogenesis and disease that causes dramatic changes in cell morphology, migration, proliferation, and gene expression. The retinal pigment epithelium (RPE), which supports the neural retina, can undergo EMT, producing fibrous epiretinal membranes (ERMs) associated with vision-impairing clinical conditions, such as macular pucker and proliferative vitreoretinopathy (PVR). We found that co-treatment with TGF-β and TNF-α (TNT) accelerates EMT in adult human RPE stem cell-derived RPE cell cultures. We captured the global epigenomic and transcriptional changes elicited by TNT treatment of RPE and identified putative active enhancers associated with actively transcribed genes, including a set of upregulated transcription factors that are candidate regulators. We found that the vitamin B derivative nicotinamide downregulates these key transcriptional changes, and inhibits and partially reverses RPE EMT, revealing potential therapeutic routes to benefit patients with ERM, macular pucker and PVR.

上皮到间质转化（EMT）是涉及组织形态发生和疾病的生物过程，导致细胞形态、迁移、增殖和基因表达发生巨大变化。支持神经视网膜的视网膜色素上皮 (RPE) 可以经历 EMT，产生与视力受损的临床病症相关的纤维视网膜前膜 (ERM)，例如黄斑皱褶和增殖性玻璃体视网膜病变 (PVR)。我们发现，TGF-β 和 TNF-α (TNT) 联合治疗可加速成人 RPE 干细胞衍生的 RPE 细胞培养物的 EMT。我们捕获了 RPE 的 TNT 处理引起的整体表观基因组和转录变化，并鉴定了与活跃转录基因相关的假定活性增强子，包括一组作为候选调节因子的上调转录因子。我们发现维生素 B 衍生物烟酰胺下调这些关键的转录变化，并抑制和部分逆转 RPE EMT，揭示了使 ERM、黄斑皱褶和 PVR 患者受益的潜在治疗途径。