David Gamm, MD, PhD, in the lab. (Image courtesy of University of Wisconsin-Madison)
Retinal cells grown from stem cells can stretch and connect with neighbors, completing a “handshake” that may indicate the cells are ready for trials in people with degenerative eye disorders, according to a new study.
More than a decade ago, researchers at the University of Wisconsin-Madison developed a way to grow organized clusters of cells, called organoids, that resemble the retina, the light-sensitive tissue at the back of the eye, according to a news release. They coaxed human skin cells reprogrammed to act like 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 these organoids as replacements for the same types of cells that are lost in the course of retinal disease,” said David Gamm, a UW-Madison professor of ophthalmology and director of the McPherson Eye Research Institute, whose lab developed the organoids. “But after months of being grown in a lab dish as compact clumps, the question remained – would the cells behave properly when we ripped them apart?” Because that’s key to getting them into the patient’s eye.”
According to a press release, during 2022, Gamm and UW-Madison collaborators published studies showing that dish-grown retinal cells called photoreceptors responded like healthy retinal cells to different wavelengths and intensities of light, and that once separated from neighboring cells. in their organoid, they can reach out to new neighbors with characteristic biological cords called axons.
“The last piece of the puzzle was to see if these cords had the ability to engage with other types of retinal cells or shake hands with them to communicate,” added Gamm, whose new results on successful cell-to-cell connections are forthcoming. in Proceedings of the National Academy of Sciences.
Cells in the retina and brain communicate through synapses, tiny gaps at the ends of their cords. To confirm that their lab-grown retinal cells had the ability to replace diseased cells and transmit sensory information like healthy ones, the researchers had to demonstrate that they could form synapses.
Xinyu Zhao, PhD, a UW-Madison professor of neuroscience and co-author of the new study, worked with Gamm’s lab cells to help study their ability to form synaptic connections. They did this by using a modified rabies virus to identify pairs of cells that could form a means of communicating with each other.
The research team, including graduate students and co-authors Allison Ludwig and Steven Mayerl, split retinal organoids into single cells, gave them a week to extend their axons and form new connections, exposed them to the virus, and then took a look. What they saw were many retinal cells labeled with fluorescent dye, indicating that one had contracted the rabies infection through a synapse successfully formed between neighbors.
“We stitched this story together in the lab, one piece at a time, to make sure we were going in the right direction,” said Gamm, who patented the organoids and co-founded Madison-based Opsis Therapeutics. which adapts technology to treat disorders of the human eye based on UW–Madison discoveries. “All of this ultimately leads to human clinical trials, which are the obvious next step.”
After confirming the presence of synaptic connections, the researchers analyzed the cells involved and found that the most common types of retinal cells forming synapses were photoreceptors—rods and cones—which are lost in diseases such as retinitis pigmentosa and age-related macular degeneration. as with some eye injuries. The next most common cell type, retinal ganglion cells, are degenerated in optic nerve disorders such as glaucoma.
“It was an important revelation for us,” Gamm concluded. “It really shows the potentially broad impact that these retinal organoids could have.”
This research was supported by federal grants from the National Institutes of Health (U01EY027266, U24EY029890, MH116582, U54HD090256, P50HD105353, and F30EY031230), the Department of Defense (W81XWH-2030), Lee Eye Research, S. and RRF Emmett A. Humble Distinguished Director of McPherson ERI .
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