Bioengineering Human Pluripotent Stem Cell-Derived Retinal Organoids and Optic Vesicle-Containing Brain Organoids for Ocular Diseases

Overview

Journal Cells

Publisher MDPI

Specialties Biochemistry
Biophysics
Cell Biology
Molecular Biology

Date 2022 Nov 11

PMID 36359825

Authors

Peggy Arthur

Laureana Muok

Aakash Nathani

Eric Z Zeng

Li Sun

Yan Li

Mandip Singh

Affiliations

Soon will be listed here.

Abstract

Retinal organoids are three-dimensional (3D) structures derived from human pluripotent stem cells (hPSCs) that mimic the retina's spatial and temporal differentiation, making them useful as in vitro retinal development models. Retinal organoids can be assembled with brain organoids, the 3D self-assembled aggregates derived from hPSCs containing different cell types and cytoarchitectures that resemble the human embryonic brain. Recent studies have shown the development of optic cups in brain organoids. The cellular components of a developing optic vesicle-containing organoids include primitive corneal epithelial and lens-like cells, retinal pigment epithelia, retinal progenitor cells, axon-like projections, and electrically active neuronal networks. The importance of retinal organoids in ocular diseases such as age-related macular degeneration, Stargardt disease, retinitis pigmentosa, and diabetic retinopathy are described in this review. This review highlights current developments in retinal organoid techniques, and their applications in ocular conditions such as disease modeling, gene therapy, drug screening and development. In addition, recent advancements in utilizing extracellular vesicles secreted by retinal organoids for ocular disease treatments are summarized.

Citing Articles

Single-cell sequencing in diabetic retinopathy: progress and prospects.

Yang T, Zhang N, Yang N J Transl Med. 2025; 23(1):49.

PMID: 39806376 PMC: 11727737. DOI: 10.1186/s12967-024-06066-x.

Optimized Prime Editing of Human Induced Pluripotent Stem Cells to Efficiently Generate Isogenic Models of Mendelian Diseases.

Cerna-Chavez R, Ortega-Gasco A, Azhar Baig H, Ehrenreich N, Metais T, Scandura M Int J Mol Sci. 2025; 26(1.

PMID: 39795970 PMC: 11719581. DOI: 10.3390/ijms26010114.

Organoids and organoid extracellular vesicles-based disease treatment strategies.

Zhou G, Li R, Sheng S, Huang J, Zhou F, Wei Y J Nanobiotechnology. 2024; 22(1):679.

PMID: 39506799 PMC: 11542470. DOI: 10.1186/s12951-024-02917-3.

Extracellular vesicles - on the cusp of a new language in the biological sciences.

Raposo G, Stahl P Extracell Vesicles Circ Nucl Acids. 2024; 4(2):240-254.

PMID: 38288044 PMC: 10824536. DOI: 10.20517/evcna.2023.18.

The Healthy and Diseased Retina Seen through Neuron-Glia Interactions.

Tempone M, Borges-Martins V, Cesar F, Alexandrino-Mattos D, de Figueiredo C, Raony I Int J Mol Sci. 2024; 25(2).

PMID: 38256192 PMC: 10817105. DOI: 10.3390/ijms25021120.

References

Kimberling W, Hildebrand M, Shearer A, Jensen M, Halder J, Trzupek K . Frequency of Usher syndrome in two pediatric populations: Implications for genetic screening of deaf and hard of hearing children. Genet Med. 2010; 12(8):512-6. PMC: 3131500. DOI: 10.1097/GIM.0b013e3181e5afb8. View

VanderWall K, Huang K, Pan Y, Lavekar S, Fligor C, Allsop A . Retinal Ganglion Cells With a Glaucoma OPTN(E50K) Mutation Exhibit Neurodegenerative Phenotypes when Derived from Three-Dimensional Retinal Organoids. Stem Cell Reports. 2020; 15(1):52-66. PMC: 7363877. DOI: 10.1016/j.stemcr.2020.05.009. View

Yu Y, Li L, Lin S, Hu J . Update of application of olfactory ensheathing cells and stem cells/exosomes in the treatment of retinal disorders. Stem Cell Res Ther. 2022; 13(1):11. PMC: 8751324. DOI: 10.1186/s13287-021-02685-z. View

Knudsen E, Sexton C, Mayhew C . Role of the retinoblastoma tumor suppressor in the maintenance of genome integrity. Curr Mol Med. 2006; 6(7):749-57. DOI: 10.2174/1566524010606070749. View

Marzano M, Bou-Dargham M, Cone A, York S, Helsper S, Grant S . Biogenesis of Extracellular Vesicles Produced from Human-Stem-Cell-Derived Cortical Spheroids Exposed to Iron Oxides. ACS Biomater Sci Eng. 2021; 7(3):1111-1122. PMC: 8185622. DOI: 10.1021/acsbiomaterials.0c01286. View

Zhang J, Gray J, Wu L, Leone G, Rowan S, Cepko C . Rb regulates proliferation and rod photoreceptor development in the mouse retina. Nat Genet. 2004; 36(4):351-60. DOI: 10.1038/ng1318. View

Phillips M, Jiang P, Howden S, Barney P, Min J, York N . A Novel Approach to Single Cell RNA-Sequence Analysis Facilitates In Silico Gene Reporting of Human Pluripotent Stem Cell-Derived Retinal Cell Types. Stem Cells. 2017; 36(3):313-324. PMC: 5823737. DOI: 10.1002/stem.2755. View

Gitler A, Dhillon P, Shorter J . Neurodegenerative disease: models, mechanisms, and a new hope. Dis Model Mech. 2017; 10(5):499-502. PMC: 5451177. DOI: 10.1242/dmm.030205. View

Lukovic D, Castro A, Kaya K, Munezero D, Gieser L, Davo-Martinez C . Retinal Organoids derived from hiPSCs of an AIPL1-LCA Patient Maintain Cytoarchitecture despite Reduced levels of Mutant AIPL1. Sci Rep. 2020; 10(1):5426. PMC: 7096529. DOI: 10.1038/s41598-020-62047-2. View

10.

Jeske R, Bejoy J, Marzano M, Li Y . Human Pluripotent Stem Cell-Derived Extracellular Vesicles: Characteristics and Applications. Tissue Eng Part B Rev. 2019; 26(2):129-144. PMC: 7187972. DOI: 10.1089/ten.TEB.2019.0252. View

11.

Arthur P, Patel N, Surapaneni S, Mondal A, Gebeyehu A, Bagde A . Targeting lung cancer stem cells using combination of Tel and Docetaxel liposomes in 3D cultures and tumor xenografts. Toxicol Appl Pharmacol. 2020; 401:115112. PMC: 7437978. DOI: 10.1016/j.taap.2020.115112. View

12.

Grytz R, Fazio M, Girard M, Libertiaux V, Bruno L, Gardiner S . Material properties of the posterior human sclera. J Mech Behav Biomed Mater. 2013; 29:602-17. PMC: 3778040. DOI: 10.1016/j.jmbbm.2013.03.027. View

13.

Klingeborn M, Dismuke W, Skiba N, Kelly U, Stamer W, Bowes Rickman C . Directional Exosome Proteomes Reflect Polarity-Specific Functions in Retinal Pigmented Epithelium Monolayers. Sci Rep. 2017; 7(1):4901. PMC: 5501811. DOI: 10.1038/s41598-017-05102-9. View

14.

HEYMAN R, Mangelsdorf D, Dyck J, Stein R, Eichele G, Evans R . 9-cis retinoic acid is a high affinity ligand for the retinoid X receptor. Cell. 1992; 68(2):397-406. DOI: 10.1016/0092-8674(92)90479-v. View

15.

Gabriel E, Albanna W, Pasquini G, Ramani A, Josipovic N, Mariappan A . Human brain organoids assemble functionally integrated bilateral optic vesicles. Cell Stem Cell. 2021; 28(10):1740-1757.e8. DOI: 10.1016/j.stem.2021.07.010. View

16.

Reichman S, Slembrouck A, Gagliardi G, Chaffiol A, Terray A, Nanteau C . Generation of Storable Retinal Organoids and Retinal Pigmented Epithelium from Adherent Human iPS Cells in Xeno-Free and Feeder-Free Conditions. Stem Cells. 2017; 35(5):1176-1188. DOI: 10.1002/stem.2586. View

17.

Muffat J, Li Y, Jaenisch R . CNS disease models with human pluripotent stem cells in the CRISPR age. Curr Opin Cell Biol. 2016; 43:96-103. DOI: 10.1016/j.ceb.2016.10.001. View

18.

Shah S, Taylor A, Sowden J, Ragge N, Russell-Eggitt I, Rahi J . Anophthalmos, microphthalmos, and typical coloboma in the United Kingdom: a prospective study of incidence and risk. Invest Ophthalmol Vis Sci. 2010; 52(1):558-64. DOI: 10.1167/iovs.10-5263. View

19.

Miyamoto A, Wake H, Ishikawa A, Eto K, Shibata K, Murakoshi H . Microglia contact induces synapse formation in developing somatosensory cortex. Nat Commun. 2016; 7:12540. PMC: 5007295. DOI: 10.1038/ncomms12540. View

20.

Tucker B, Park I, Qi S, Klassen H, Jiang C, Yao J . Transplantation of adult mouse iPS cell-derived photoreceptor precursors restores retinal structure and function in degenerative mice. PLoS One. 2011; 6(4):e18992. PMC: 3084746. DOI: 10.1371/journal.pone.0018992. View