A new study reveals how photoreceptors grown from stem cells might extend biological wires, known as axons, to contact existing neurons.
The finding has implications for future treatment of retinal diseases that cause blindness, including age-related macular degeneration and rare diseases such as retinitis pigmentosa, Usher syndrome, Stargardt disease and Best disease.
People living with these diseases, which are currently uncurable, ultimately lose vision due to destruction of light sensitive cells called rods and cones. Neuroscientists are working on therapies to grow these cells, also known as photoreceptors, from stem cells and transplant them to restore damaged tissue.
However, while the ability to manufacture lab-grown photoreceptors has advanced considerably, it remains challenging to “install” them. Once transplanted, the photoreceptors must grow axons to connect with existing inner neurons so the light they detect is transmitted via signals to the brain.
The University of Wisconsin School of Medicine and Public Health research team showed that photoreceptors derived from stem cells are initially able to grow axons on their own to connect to other cells but lose that ability within 40 to 80 days. However, they found that mobile helper cells can assist photoreceptors that are no longer able of independently growing axons by pulling and dramatically stretching parts of them.
“Understanding how photoreceptors reach out to make these connections brings us another step closer to being able to transplant stem–cell derived photoreceptors to cure blindness,’’ said Timothy Gomez, professor of neuroscience at the school, and the study’s senior author.
Sarah Rempel, a postdoctoral researcher who led the study and works in the Gomez lab, collaborated with the research team led by co-author Dr. David Gamm, professor of ophthalmology and visual science to successfully generate retinal organoids. Retinal organoids are three-dimensional models of the retina derived from human pluripotent stem cells.
As the organoids developed, the human pluripotent stem cell-derived photoreceptors began to produce cone cells, which are critical for human daytime vision. This started around day 30. They also produced rod cells, which allow vision in low-light conditions, which began around day 70.
Then the team used time-lapse imaging of the living cells to watch as the axons extended from the photoreceptors toward their target cells. While the ends of recently generated cone photoreceptor axons could actively elongate, their window to do so was surprisingly short; by day 80 they lost this ability. Rod photoreceptors, in contrast, completely lacked the ability to extend axons on their own.
The team discovered that older laboratory-grown photoreceptor cells could extend axons to make connections if they were grown along with other, motile retinal cells. Unexpectedly, axons of the photoreceptor cells could attach themselves to these cells and be pulled along for the ride.
The team is also exploring the possibility of encouraging remaining retinal cells targeted by newly transplanted photoreceptors to reach out as well.
The study is an important step in developing stem cell therapies for blindness, said Gamm, who is also director of the McPherson Eye Research Institute and an expert in retinal stem cells and their applications to human disease.
“Work here at UW–Madison is really converging on this field,” he explained. “We are beginning to understand core principles of how we might replace photoreceptor cells in people with advanced stages of blinding disease.”
Other members of the research team include Madalynn Welch, Allison Ludwig, M. Joseph Phillips and Yochana Kancherla from the UW School of Medicine and Public Health, and Dr. Donald Zack of Johns Hopkins University.
The work was supported by a grant from the National Eye Institute Audacious Goals Initiative, which is aimed at regenerating photoreceptors and other cell types in the human retina.
Additional funding was provided by the National Institute of Neurological Disorders and Stroke (5R01 NS113314-02, 5R01 NS041564, and 1R21 NS113314-01A1), the National Eye Institute (NEI) ( U01 EY027266-01 ), the Retina Research Foundation Emmett Humble Chair, the Sarah E. Slack Prevention of Blindness Fund (a component fund of the Muskingum County Community Foundation), the McPherson Eye Research Institute Sandra Lemke Trout Chair in Eye Research, the Guerrieri Family Foundation, and Research to Prevent Blindness, a core grant to the Waisman Center (NICHHD U54 HD090256), NEI grant T32 EY027721, the UW-Madison School of Veterinary Medicine DVM/PhD Program, NEI grant U24 EY029890, and a Kirschstein NRSA Predoctoral Fellowship ( NEI grant F30 EY031230 ).