Large Scale Generation of Light-Responsive Human Retinal Organoids

Source: Stem Cells

In a new study published by Stem Cells, researchers at Newcastle University, UK, describe a new organoid model that encompasses all human retinal cell types and that is responsive to light. Their work could have great impact on finding new treatments for the visually impaired by making drug and toxicology screening faster and more efficient.

The number of people worldwide affected by visual impairment is massive—currently estimated at 285 million—and continues to rise as life expectancy increases. Many of those affected are older people, suffering from diseases such as age-related macular degeneration (AMD), retinitis pigmentosa (RP), and glaucoma.

Until now, most drug studies aimed at finding treatments for these diseases are performed on rodent models, a situation that is far from ideal due to the fundamental structural and functional differences between a rodent’s and a human’s retina.

Recent studies by other researchers have shown the promise of iPSCs in producing “workable” light-responsive 3-D retinal cell models. To date, however, these organoids have not been used extensively in toxicology or pharmacology screening due largely to the lack of differentiation methods that generate them in numbers large enough for this type of testing.

The Newcastle University team addressed this issue by investigating five separate human iPSC lines to determine their ability to generate such retina. “In particular we wanted to gauge the organoids’ capacity for large-scale automation and drug screening as well as their usefulness in toxicity screening programs,” said the study’s corresponding author, Majlinda Lako, PhD, professor of stem cell sciences in Newcastle University’s Institute for Genetic Medicine.

Three of the five cell lines in the study came from healthy donors, while the other two were from diseased subjects—one with AMD and the other with RP. Despite this, all five lines generated light-responsive retinal organoids, although they showed significant variability in their overall efficiency to do so. Additionally, by month 5 each organoid produced from the lines responded to light at a level comparable to that recorded in neonatal mice retina close to the time of eye opening.

“This variability in the lines’ efficiency cannot be related solely to disease pathology as it was encountered also between iPSC lines from unaffected individuals,” Dr. Lako noted. “Seeding density and nutrient availability seemed to have had the most dominant effect on retinal organoid formation.

“Overall, our study affirms that light-responsive retinal organoids derived from carefully selected and differentiation efficient iPSC lines can be generated at a scale needed for pharmacology and drug screening purposes.”

Through statistical design experiment, the authors determined the optimal application of key growth factors, small molecules and cell seeding density to generate light and drug responsive laminated retinal organoids in a multi well plate format that allows scalability and automation.

Editor-in-Chief of Stem Cells, Dr. Jan Nolta, commented, “We congratulate Dr. Lako and her team on the development of light-sensing 3-D organoids containing all human retinal types, which can significantly enhance the development of therapy for blindness.”

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