Researchers from the University of Wisconsin School of Medicine and Public Health have successfully shown that a retinal cell type derived from human pluripotent stem cells is capable of the complex process of detecting light and converting that signal to electrical waves.

These organoid cone photoreceptors – which are laboratory-produced versions of light-responsive eye tissue – are similar to cones in the primate fovea, a specialized area of the eye responsible for high-definition vision.

It’s the first time that cone photoreceptors derived from stem cells exhibited the ability to respond to light and the results, recently published in the journal Cell Stem Cell, could unlock new therapeutic avenues for treating vision loss. Retinal organoids could eventually serve as replacement sources for human photoreceptor cells.

Raunak Sinha portrait
Raunak Sinha

“For diseases like macular degeneration where cones in the central-most part of the retina die, causing blindness, there are currently no treatment options,” says study author and UW–Madison neuroscience professor Raunak Sinha, PhD. “But with the advent of stem cell technology, you can make these stem cells grow into three-dimensional mini retinas containing cones that can replicate the physiology and function of foveal cones.” 

David Gamm
David Gamm

For more than 20 years, UW–Madison has been a pioneer in the discovery and study of human stem cells, and study co-author David Gamm, MD, PhD, has been on the forefront of creating three-dimensional retinal tissues known as retinal organoids. 

“These retinal organoids look remarkably similar to real human retinas,” says Gamm, director of the McPherson Eye Research Institute. “They’ve got the correct cell types and the necessary sub-cellular structures to function appropriately. But it remained uncertain whether they could adequately replicate that fundamental feature of the retina, which is to detect light.”

Generating functional human photoreceptors in a dish is a complex process, but previous studies offered some tantalizing evidence that retinal organoids could get the job done. At issue are photoreceptor cells – rods and cones – which are key to vision. Both are found in the retina, with rods handling dim light and peripheral vision and cones handling brighter light, color, and high acuity vision.

Up until now, scientists had been unable to generate light-evoked electrical responses in retinal organoid photoreceptors that compared in strength to those measured in photoreceptors in intact primate retinas.

In their most recent study – a collaboration between the UW–Madison Department of Neuroscience and Department of Ophthalmology and Visual Sciences as well as the McPherson Eye Research Institute – Sinha and Gamm looked at cone photoreceptors from many different retinal organoids that were allowed to mature in the lab for roughly eight months to ensure uniformity.

Using advanced electrophysiological techniques to analyze electrical activity, the researchers were able to demonstrate robust, graded, color-specific light responses in the organoid cones. Additionally, the lab-cultured cells functioned on par with cones present in the fovea.

mature retinal organoid
A mature retinal organoid (left) and its cone photoreceptors

“We went from important early studies showing weak light responses in rod photoreceptors that mediate dim light vision to seeing the potential for responses to light in the cone cells that humans rely on the most,” Gamm says. “The cells responded robustly, and could differentiate between red, green and blue light, just like in normal human cones. It’s really quite remarkable.”

Sinha and Gamm have now turned their efforts toward improving the retinal organoids’ light-evoked electrical responses, and bringing them closer to the performance of actual human fovea.

“We’ve shown very promising sensitivity, but there is room to improve,” Sinha says. “The immediate next step for us is to try and figure out how can we improve the sensitivity of these cones and what the missing components are in these organoids.”

Beyond that, Sinha and Gamm’s team – including researchers Aindrila Saha and Beth Capowski – will apply their findings to organoid models that resemble retinas with degenerative disease, such as retinitis pigmentosa or macular degeneration.

“Using these patient-derived retinal organoids, we’ll use what we’ve learned to understand how retinal diseases impact the cellular function of photoreceptors and use viral-mediated gene delivery to see if we can restore normal function,” Sinha says. “That will give us key information that could eventually set the stage for a clinical trial.”

Gamm adds, “The more we can push retina organoids to perform at a high level in a [cell culture] dish, the more confidence we have that they may help patients with blinding disorders. So, it’s a big leap in human pluripotent stem cell technology in terms of its applications to retinal disease.”