Antioxidant and lipid supplementation improve the development of photoreceptor outer segments in pluripotent stem cell-derived retinal organoids

• Published in: Stem cell reports 2022-04, Vol.17 (4), p.775-788
• Main Authors: West, Emma L., Majumder, Paromita, Naeem, Arifa, Fernando, Milan, O'Hara-Wright, Michelle, Lanning, Emily, Kloc, Magdalena, Ribeiro, Joana, Ovando-Roche, Patrick, Shum, Ian O., Jumbu, Neeraj, Sampson, Robert, Hayes, Matt, Bainbridge, James W.B., Georgiadis, Anastasios, Smith, Alexander J., Gonzalez-Cordero, Anai, Ali, Robin R.
• Format: Article
• Language: English
• Subjects: Antioxidants - pharmacology; degeneration; Dietary Supplements; disease modeling; docosahexaenoic acid; gene therapy; Humans; induced pluripotent stem cells; Lipids; Organoids; outer segments; photoreceptors; Pluripotent Stem Cells; Retina; Retinal Cone Photoreceptor Cells; retinal organoids; retinitis pigmentosa; RPGR
• ISSN: 2213-6711; 2213-6711
• DOI: 10.1016/j.stemcr.2022.02.019

The generation of retinal organoids from human pluripotent stem cells (hPSC) is now a well-established process that in part recapitulates retinal development. However, hPSC-derived photoreceptors that exhibit well-organized outer segment structures have yet to be observed. To facilitate improved inherited retinal disease modeling, we determined conditions that would support outer segment development in maturing hPSC-derived photoreceptors. We established that the use of antioxidants and BSA-bound fatty acids promotes the formation of membranous outer segment-like structures. Using new protocols for hPSC-derived retinal organoid culture, we demonstrated improved outer segment formation for both rod and cone photoreceptors, including organized stacked discs. Using these enhanced conditions to generate iPSC-derived retinal organoids from patients with X-linked retinitis pigmentosa, we established robust cellular phenotypes that could be ameliorated following adeno-associated viral vector-mediated gene augmentation. These findings should aid both disease modeling and the development of therapeutic approaches for the treatment of photoreceptor disorders. [Display omitted] •Antioxidants and lipids are required for the formation of organized outer segments•Both rod and cone hPSC-derived photoreceptors generate well-formed outer segments•Improved conditions provide a robust model of X-linked retinitis pigmentosa type 3•Enhanced segment formation permits the evaluation of therapeutic interventions In this article, Ali and colleagues demonstrate the generation of hPSC-derived photoreceptors, bearing organized outer segments. Using these enhanced conditions, they report robust cellular phenotypes in an iPSC-based model of X-linked retinitis pigmentosa, which were ameliorated with gene supplementation. The findings presented will aid disease modeling of human photoreceptor-specific disorders and the development of novel therapeutic approaches.