Merging organoid and organ-on-a-chip technology to generate complex multi-layer tissue models in a human retina-on-a-chip platform

• Published in: eLife Vol. 8
• Main Authors: Achberger, Kevin, Probst, Christopher, Haderspeck, Jasmin, Bolz, Sylvia, Rogal, Julia, Chuchuy, Johanna, Nikolova, Marina, Cora, Virginia, Antkowiak, Lena, Haq, Wadood, Shen, Nian, Schenke-Layland, Katja, Ueffing, Marius, Liebau, Stefan, Loskill, Peter
• Format: Journal Article
• Language: English
• Published: England eLife Sciences Publications Ltd 27.08.2019; eLife Sciences Publications, Ltd
• Subjects: Age; Animal models; Antibiotics; Biochips; Calcium signalling; Cell culture; Chloroquine; Drug development; Embryo cells; Epithelium; Gene expression; Gentamicin; Human Biology and Medicine; human induced pulipotent stem cells; Humans; Induced Pluripotent Stem Cells - physiology; Lab-On-A-Chip Devices; Macular degeneration; Malaria; microphysiological systems; Microscopy; organ-on-a-chip; Organoids; Organoids - growth & development; Perfusion; Phagocytosis; Photoreceptors; Physiology; Pluripotency; Retina; Retina - physiology; retinal organoids; retinal pigment epithelial cell; Retinal pigment epithelium; Retinitis; Retinitis pigmentosa; Statistical analysis; Stem cell transplantation; Stem cells; Stem Cells and Regenerative Medicine; Vascularization; United States > US; Germany; California; human biology; human induced pulipotent stem cells; stem cells; microphysiological systems; regenerative medicine; medicine; organ-on-a-chip; none; retinal pigment epithelial cell; retinal organoids
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/elife.46188

The devastating effects and incurable nature of hereditary and sporadic retinal diseases such as Stargardt disease, age-related macular degeneration or retinitis pigmentosa urgently require the development of new therapeutic strategies. Additionally, a high prevalence of retinal toxicities is becoming more and more an issue of novel targeted therapeutic agents. Ophthalmologic drug development, to date, largely relies on animal models, which often do not provide results that are translatable to human patients. Hence, the establishment of sophisticated human tissue-based in vitro models is of upmost importance. The discovery of self-forming retinal organoids (ROs) derived from human embryonic stem cells (hESCs) or human induced pluripotent stem cells (hiPSCs) is a promising approach to model the complex stratified retinal tissue. Yet, ROs lack vascularization and cannot recapitulate the important physiological interactions of matured photoreceptors and the retinal pigment epithelium (RPE). In this study, we present the retina-on-a-chip (RoC), a novel microphysiological model of the human retina integrating more than seven different essential retinal cell types derived from hiPSCs. It provides vasculature-like perfusion and enables, for the first time, the recapitulation of the interaction of mature photoreceptor segments with RPE in vitro. We show that this interaction enhances the formation of outer segment-like structures and the establishment of in vivo-like physiological processes such as outer segment phagocytosis and calcium dynamics. In addition, we demonstrate the applicability of the RoC for drug testing, by reproducing the retinopathic side-effects of the anti-malaria drug chloroquine and the antibiotic gentamicin. The developed hiPSC-based RoC has the potential to promote drug development and provide new insights into the underlying pathology of retinal diseases.