A 291-day-old retina organoid. Red and green cone photoreceptors appear green, blue cone photorectors appear blue, and rod photoreceptors appear red.Johns Hopkins University
Scientists have grown simplified human retinas that appear to recapitulate human development in a dish, confirming the role of thyroid hormone in guiding light-detecting cone photoreceptor cells to become either blue-sensing or become red- or green-sensing. The new research published today suggests a potential treatment approach for premature babies with certain vision problems.
Studying how a human develops in utero is hard. It happens in a dark place, closed off from the outside world. Scientists can’t easily get samples of tissues from developing fetuses that they can take back to the lab and scrutinize to find out the biological mechanisms and molecules that make development happen. And animals like mice just aren’t quite the same as humans.
So some scientists have started using organoids, clusters of human cells coaxed to grow from stem cells into tiny, simplified model organs, to zero in on the human development process. Robert Johnston, now an assistant professor of biology at Johns Hopkins University, had been studying how the eye’s light-detecting cells, called photoreceptors, develop in fruit flies when he saw data on retinal organoids presented in 2012. “We have to push this system places no one’s gone before,” he remembers thinking, and grow the organoids for longer time periods. Research from his lab published today in Science describes experiments growing retinal organoids from six months up to a year. “This opens up an avenue as a different way to study human biology,” Johnston says.
Early on, as the retina develops, the would-be cone photoreceptors have to become one of two types of cells: one that detects blue light or one that still has the flexibility to later become a cell that detects red light or detects green light. Johnston’s team, including lead author and graduate student Kiara Eldred, focused on the blue or red/green sensing cutpoint in cells making up retinal organoids, and found that eliminating the thyroid hormone receptors in the cells resulted in tiny retinas consisting of cones that only sensed blue light. Adding more thyroid hormone resulted in only red/green cells. When left to themselves, at first all the cells become blue-sensing until “almost like a timer goes off,” Johnston says, and the rest become red/green sensing. The presence of thyroid hormone seemed to be flipping the switch.
But the dishes where the organoids grew didn’t have tiny thyroids in them, and in most of the experiments the scientists weren’t adding the hormone themselves. So how was the hormone, which in adults regulates metabolism, calling the shots on development? “The retina itself is controlling thyroid hormone [levels] to determine whether you get blue or red/green cells,” Johnston says, with its own enzymes that were either breaking down the little amount of thyroid hormone present in the liquid the organoids were growing in or converting it to its active form.
The work largely tested the model of cone development found in mice and found one key difference in human cells, said Thomas Reh, a professor of biological structure at the University of Washington, whose papers described the mouse process. In mice only one type of thyroid hormone receptor was involved, but in humans it was two. “It is not at all clear why this difference exists,” Reh wrote in an email, “but it may have important implications for understanding another key difference between mice and humans, the fovea,” a part of the retina where most cones are located and the center of the field of vision is focused.
Reh noted that organoids do not develop foveae either, and because the organoids are much smaller than human retinas and don’t develop the other cell types of the retina in the appropriate ratio to cones, the changes in thyroid hormone levels might be different in the experiments than in developing retinas. “In some ways it is amazing that developmental processes as complex as cone specification work as well as they do given the caveats,” he wrote.
Organoids may be a proxy for studying human development with fetal tissue, but they’re not entirely clear of controversy. Some of the organoids in Johnston’s paper were formed from embryonic stem cells, and some from induced pluripotent stem cells derived from adults. These days, several lines of embryonic stem cells are available for research and new ones aren’t being made, Johnston says.
His lab is now working on developing retinal organoids that can model macular degeneration, the leading cause of vision loss in which the macula—part of the retina that contains the foveae—is damaged, and perhaps figure out how to repair it. In the shorter term, the work published today hints at a possible treatment for babies born prematurely that have low thyroid hormone levels and a higher rate of problems with color vision.
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