A canine retina with xlpra2 shows how a marker of cell division (red) and rod cells (green) colocalize. Credit: Image courtesy of University of Pennsylvania
In a new study, researchers have shown retinal cells in 3 distinct forms of canine early-onset blindness possess an unexpected feature: they temporarily rejuvenate. Further investigation into the reasons for this period of retinal neuron proliferation could lead to molecular targets for intervening in cell death and maintaining functional photoreceptor cells and a working retina.
The findings suggest this feature may be common across many forms of inherited blindness. The study picked up where 2011 work left off. The Penn Vet team had found in early retinal degeneration, or erd, an inherited canine retinal disease which leaves dogs sightless within a year of birth, that photoreceptor cells in the retina continued to divide when the animals were between 7 and 14 weeks of age. “After 14 weeks, the balance between death and division tips, and the retina degenerates,” Aguirre said.
They examined 2 other early-onset blinding diseases. One is X-linked progressive retinal atrophy, or xlpra2, a disease very similar to the human disease X-linked retinitis pigmentosa, one of the most common forms of retinal degeneration. The other is rod cone dysplasia 1, or rcd1. The team wanted to know whether retinal cells were proliferating and, if they were, what specific types of cells were doing so.
Using chemical markers that label cells going through division, along with markers that only tag rod cells, the primary photoreceptor retina, Gardiner says they saw “beautiful labeling.” “To our great surprise, in these other two diseases we also saw a period of cell proliferation,” Aguirre said. While erd cells had entered a proliferation stage at 7 weeks, the researchers observed similar increases in cell division at 2 weeks in rcd1 and at 8 weeks in xlrpa2, all time points that precede or coincide with the known peaks of cell death in the three diseases.
A further experiment ruled out the possibility that the same cells that were proliferating were also then undergoing cell death. “We wanted to make sure that these weren’t some aberrant cells that were expressing all these different markers,” Gardiner said. “We showed that there appears to be a distinct population of rod cells that is proliferating and another that is dying.”
Finally, the team performed genetic and protein analyses to look for variations at these critical time periods between diseased and normal eyes. Of note, they found that changes in expression of cell cycle-related genes and proteins coincided with specific diseases stages, including expression patterns that were shared across erd, xlpra2 and rcd1.
Additional research will also narrow in on the genes involved in turning cells on to divide, with a hope of developing a therapy that could interfere with the eventual cell death and retinal degeneration that characterizes the 3 diseases studied as well as many other forms of inherited blindness. “If you have a cell that is functional but sick, perhaps we could provide it with some agent that will allow it to keep replenishing itself and maintain a functional retina for a longer period of time,” Aguirre said. https://news.upenn.edu/news/retinal-cells-die-they-regenerate-penn-vet-blindness-study-finds
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