Epigenomic and Transcriptomic Changes During Human RPE EMT in a Stem Cell Model of Epiretinal Membrane Pathogenesis and Prevention by Nicotinamide

Summary

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.

Graphical Abstract

Highlights

• •

  Human stem cell-based model of epiretinal membrane formation in RPE cells

• •

  Mapping of global epigenomic and transcriptomic changes when human RPE undergo EMT

• •

  Bioinformatic analysis identified gene networks regulating RPE in normal and EMT

• •

  Nicotinamide prevents RPE contractility and partially reverses RPE EMT

Abstract

In this article, Temple, Blenkinsop, and colleagues characterize retinal pigment epithelium (RPE) EMT both transcriptionally and epigenetically in a model of PVR and found a gene signature that predicted the inhibitory effect of nicotinamide on both RPE contractility and EMT.