Human iPSC-Derived Retinas Recapitulate the Fetal CRB1 CRB2 Complex Formation and Demonstrate that Photoreceptors and Müller Glia Are Targets of AAV5

Peter M Quinn, Thilo M Buck, Aat A Mulder, Charlotte Ohonin, C Henrique Alves, Rogier M Vos, Monika Bialecka, Tessa van Herwaarden, Elon H C van Dijk, Mays Talib, Christian Freund, Harald M M Mikkers, Rob C Hoeben, Marie-José Goumans, Camiel J F Boon, Abraham J Koster, Susana M Chuva de Sousa Lopes, Carolina R Jost, Jan Wijnholds

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Abstract

Human retinal organoids from induced pluripotent stem cells (hiPSCs) can be used to confirm the localization of proteins in retinal cell types and to test transduction and expression patterns of gene therapy vectors. Here, we compared the onset of CRB protein expression in human fetal retina with human iPSC-derived retinal organoids. We show that CRB2 protein precedes the expression of CRB1 in the developing human retina. Our data suggest the presence of CRB1 and CRB2 in human photoreceptors and Müller glial cells. Thus the fetal CRB complex formation is replicated in hiPSC-derived retina. CRB1 patient iPSC retinal organoids showed disruptions at the outer limiting membrane as found in Crb1 mutant mice. Furthermore, AAV serotype 5 (AAV5) is potent in infecting human Müller glial cells and photoreceptors in hiPSC-derived retinas and retinal explants. Our data suggest that human photoreceptors can be efficiently transduced by AAVs in the presence of photoreceptor segments.

Original languageEnglish
Pages (from-to)906-919
JournalStem Cell Reports
Volume12
DOIs
Publication statusPublished - 2019

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    Quinn, P. M., Buck, T. M., Mulder, A. A., Ohonin, C., Alves, C. H., Vos, R. M., Bialecka, M., van Herwaarden, T., van Dijk, E. H. C., Talib, M., Freund, C., Mikkers, H. M. M., Hoeben, R. C., Goumans, M-J., Boon, C. J. F., Koster, A. J., Chuva de Sousa Lopes, S. M., Jost, C. R., & Wijnholds, J. (2019). Human iPSC-Derived Retinas Recapitulate the Fetal CRB1 CRB2 Complex Formation and Demonstrate that Photoreceptors and Müller Glia Are Targets of AAV5. Stem Cell Reports, 12, 906-919. https://doi.org/10.1016/j.stemcr.2019.03.002