Parallels Found Between Metabolic Changes in AMD and Liver Cells

What: Cells' transition from one state to another is often accompanied by changes in gene expression and protein modification. Understanding these changes gives deep insight into how the cells function in normal and pathological states. New research funded by BrightFocus identifies molecular alterations that occur when cells in the retinal pigment epithelium (RPE) transition to a mesenchymal state – a change that enables them to migrate and can contribute to age-related macular degeneration (AMD). Although cell transition is part of the normal cellular process but is also a process that is activated in cancer cells. The researchers also found similar modifications in liver cells. Their findings of linked metabolic pathways clears a path to discover new treatments for a variety of RPE diseases including AMD.

Where: Mertz JL et al. Proteomic and Phosphoproteomic Analyses Identify Liver-Related Signaling in Retinal Pigment Epithelial Cells During EMT, Cell Reports, 2021

BrightFocus Connection: This research was funded in part by a BrightFocus funding to Donald Zack, MD, PhD, of the Wilmer Eye Institute at Johns Hopkins. Dr. Zack is a past grantee in both the Macular Degeneration Research (MDR) and National Glaucoma Research (NGR) programs. He was featured in the Baltimore Sun for his successful attempts to “grow” bioengineered stem cells into retinal ganglion cells, which are damaged in glaucoma. The study also includes another MDR grantee Dr. Noriko Esumi, funded to study the role of inflammation in AMD.

Why It Is Important: The retinal pigment epithelium, or RPE, is a layer of cells in the retina. It lies between photoreceptors, which convert light to electrical signals, and the choroid, tissue laced with blood vessels that nourish and maintain the retina. Under normal conditions, the cells in the RPE are shaped like cobblestones and fit tightly together. However, under a process known as epithelial-mesenchymal transition (EMT), RPE cells lose their shape, separate from each other, and begin to move about.

EMT occurs throughout the body, not only in the retina. It enables healthy processes such as embryo development, tissue regeneration, and wound healing, and it can also play a role in disease states, such as cancer and AMD, where EMT leads to structural disruption and development of fibrous tissue under the retina.

As RPE cells transition from an epithelial to a mesenchymal state, there are two notable changes: the cells express different genes, and cell proteins alter their shape, function, and signaling pathways through phosphorylation, or the acquisition of a phosphate molecule.

For this work, the researchers studied large-scale changes in protein expression (proteomics) and protein phosphorylation (phosphoproteomics) of RPE cells undergoing EMT. They induced EMT in RPE cells derived from human induced pluripotent stem cells (iPSC), then created portraits of protein expression and phosphorylation exhibited by the cells at both 1 hour and 12 hours after EMT induction. They identified over 8,000 proteins and over 9,000 phosphorylated proteins.

The researchers then compared their findings against similar studies of other types of cells undergoing different transitional states, such as proliferation of liver cells and cancer of the liver. They focused on one particular signaling pathway because it was highlighted in their analyses and is associated with EMT transition in both cancer and RPE cells. They found that RPE cells undergoing EMT show gene expression and cellular signaling similar to cells implicated in liver tumor, cancer, and carcinoma.

The researchers’ extensive database provides insight into the molecular function of RPE cells undergoing EMT. It illuminates the role they play in other retinal diseases besides AMD, including proliferative vitreoretinopathy, a complication that occurs after retinal detachment, and encourages exploration into new treatments.