Retinal cells grown from stem cells can reach out and connect with neighbours, completing a ‘handshake’ that may show the cells are ready for trials in humans with degenerative eye disorders.
The finding from the new study is the last piece in a puzzle that researchers from the University of Wisconsin-Madison (UW–Madison) have been working on for more than 10 years.
Over a decade ago, researchers from UW–Madison developed a way to grow organised clusters of cells, called organoids, that resemble the retina, the light-sensitive tissue at the back of the eye.
They coaxed human skin cells, reprogrammed to act as stem cells, to develop into layers of several types of retinal cells that sense light and ultimately transmit what we see to the brain.
“We wanted to use the cells from those organoids as replacement parts for the same types of cells that have been lost in the course of retinal diseases,” said Professor David Gamm from the UW–Madison’s McPherson Eye Research Institute.
“But after being grown in a laboratory dish for months as compact clusters, the question remained – will the cells behave appropriately after we tease them apart? Because that is key to introducing them into a patient’s eye,” he said.
The last piece of the puzzle was to see if these cords had the ability to plug into, or shake hands with, other retinal cell types in order to communicate
LAST PIECES OF PUZZLE
During 2022, Prof Gamm and colleagues published studies showing that dish-grown retinal cells called photoreceptors respond like those in a healthy retina to different wavelengths and intensities of light, and that once they are separated from adjacent cells in their organoid, they can reach out toward new neighbours with characteristic biological cords called axons.
“The last piece of the puzzle was to see if these cords had the ability to plug into, or shake hands with, other retinal cell types in order to communicate,” said Prof Gamm.
To confirm that their lab-grown retinal cells have the capacity to replace diseased cells and carry sensory information like healthy ones, the researchers needed to show that they could make synapses.
Professor Xinyu Zhao, UW–Madison professor of neuroscience and co-author of the new study, worked with the Gamm lab’s cells to help study their ability to form synaptic connections. They did this using a modified rabies virus to identify pairs of cells that could form the means to communicate with one another.
The research team broke apart the retinal organoids into individual cells, gave them a week to extend their axons and make new connections, then exposed them to the virus. What they saw were many retinal cells marked by a fluorescent colour indicating a rabies infection had infected one across a synapse successfully formed between neighbours.
“We’ve been quilting this story together in the lab, one piece at a time, to build confidence that we’re headed in the right direction,” said Prof Gamm.
“It’s all leading, ultimately, to human clinical trials, which are the clear next step.”
After they confirmed the presence of synaptic connections, the researchers analysed the cells involved and found that the most common retinal cell types forming synapses were photoreceptors – rods and cones – which are lost in diseases like retinitis pigmentosa and age-related macular degeneration. The next most common cell type, retinal ganglion cells, are degenerate in optic nerve disorders like glaucoma.
“That was an important revelation for us,” said Prof Gamm. “It really shows the potentially broad impact these retinal organoids could have.”
Ludwig, A.L., Mayeri, S.J., Gao, Y., Gamm, D.M., et al., Reformation of synaptic connectivity in dissociated human stem cell-derived retinal organoid cultures published in Proceedings of the National Academy of Sciences, 120 (2) e2213418120: https://doi.org/10.1073/pnas.2213418120.