Regrowing the Retina
Researcher Uncovers ‘Roadmap’ to RPE Regeneration
What if we could cure diseases such as age-related macular degeneration (AMD) by regrowing the damaged parts of the eye? Researchers like Dr. Katia Del Rio-Tsonis of Miami University are working to make it possible.
In her recent lecture, “Uncovering the Roadmap Toward Retinal Regeneration via RPE Reprogramming,” Del Rio-Tsonis discussed her research as part of the NEI Audacious Goals seminar series in neuroregeneration. The talks explore regenerative neuroscience and medicine with special emphasis on the visual system.
The RPE is the retinal pigment epithelium, a structure in the eye composed of a single layer of cells at the outermost layer of the retina. In AMD, the RPE begins to degenerate, causing vision loss. RPE reprogramming is “the window to the future of the [Audacious Goals Initiative],” said seminar host Dr. Tom Greenwell, acting associate director of NEI’s Office of Regenerative Medicine.
Del Rio-Tsonis’s research focuses on the cellular and molecular events that occur during retina and lens regeneration. She uses animal models such as newts, frogs and chickens as well as human-induced pluripotent stem cells (iPSCs).
Some adult salamanders have the remarkable ability to regrow their lens and retina (and just about any other bodily tissue) after removal—a feat that is unheard of for most adult animals, Del Rio-Tsonis said.
Regrowing the retina in newts occurs through RPE cell de-differentiation. Cells “reprogram” and transform into two kinds of progenitor cells (descendants of stem cells that can further change into specialized cell types). Neural progenitor cells replace the neural retina (one of two layers that form the complete retina) and RPE progenitors replace the RPE itself.
The ability to transition from one adult cell type to another is unique and involves specific regulation at the gene level. Del Rio-Tsonis wants to learn how to harness that regenerative power for humans, to be applied to conditions such as AMD.
Early-stage embryos also can regrow body parts under the right conditions. Del Rio-Tsonis studies the phenomenon in embryonic chickens (chicks). She has found that, within a narrow window of time, the chicks can regrow their retina after its removal (retinectomy) by reprogramming the RPE.
In her research, she removes the retina from a four-day-old chick embryo, leaving the RPE and ciliary margin intact. Adding fibroblast growth factor 2 (FGF2) induces “robust regeneration,” with RPE cells reprogramming into a neuroepithelium, which eventually differentiates into mature retina neurons and muller glia. FGF2 is vital to this process—without it, the retina does not regenerate.
Additionally, Del Rio-Tsonis has learned that there is only a small window of opportunity for embryonic RPE regeneration. The RPE is considered “plastic,” or able to reprogram, at embryonic day four (called “E4”), but that plasticity is lost at day five, or E5.
“The RPE will not reprogram, even with FGF2,” she explained. At E5, the RPE becomes “fate-restricted” rather than plastic.
Del Rio-Tsonis also studies the genetics of RPE regeneration. She observed that the “RPE genetic landscape changes as it responds to injury and FGF2.”
She examined the genetic profiles of chick RPEs within 6 hours of removal—with and without adding FGF2. She found that “key neural transcription factors [including genes like VSX2 and SIX6] remain FGF2-inducible past the window of RPE competency restriction.”
This is not true for all transcription factors in the RPE, though; the RPE functional program present at E5 is not disrupted with FGF2 and this program is driven by key transcription factors such as OTX2 and MITF.
Through single nuclei RNAseq, she identified several novel players that could dictate RPE regeneration competence. These genes may be helpful for future research for prompting RPE regeneration past E4.
Future steps, Del Rio-Tsonis said, include expanding these gene expression studies to human iPSC-derived RPE model systems.
A recording of the lecture is available at https://bit.ly/3Dbilnc.