A team of scientists led by the National Eye Institute (NEI) has used patient stem cells and 3D bioprinting to produce eye tissue that could advance our understanding of age-related blinding diseases. The experts printed a combination of cells which form the outer blood-retina barrier and support the retina’s light-sensing photoreceptors. This method provides a technically unlimited supply of patient-derived eye tissue to study degenerative retinal diseases, such as age-related macular degeneration (AMD).
“We know that AMD starts in the outer blood-retina barrier,” said study senior author Kapil Bharti, the head of the NEI Section on Ocular and Stem Cell Translational Research. “However, mechanisms of AMD initiation and progression to advanced dry and wet stages remain poorly understood due to the lack of physiologically relevant human models.”
The outer blood-retina barrier consists of the retinal pigment epithelium (RPE), which is separated by Bruch’s membrane from the blood-vessel rich choriocapillaris. This membrane plays a fundamental role in regulating the exchange of both nutrients and waste between the choriocapillaris and the RPE. In individuals suffering from AMD, lipoprotein deposits (called “drusen”) form outside the membrane, impeding its function, and, over time, the RPE break down leading to the degeneration of photoreceptors and, ultimately, to vision loss.
The scientists combined three immature choroidal cell types in a hydrogel: pericytes and endothelial cells (which are critical components of capillaries), and fibroblasts, which give tissues structure. Then, they printed the gel on a biodegradable scaffold and noticed that, in just a few days, the cells began to mature into a dense capillary network. On day nine, the researchers seeded retinal pigment epithelial cells on the opposite side of the scaffold.
The printed tissue reached full maturity on day 42, and began looking and behaving similarly to native outer blood-retina barrier. Under induced stress, this printed tissue exhibited patterns of early AMD, such as drusen deposits beneath the RPE, followed by progression to late dry stage AMD, characterized by widespread tissue degradation. Keeping this tissue under low oxygen conditions induced wet AMD-like appearance, with a massive proliferation of choroidal vessels which migrated into the sub-RPE zone. However, by using anti-VEGF drugs, which are employed by physicians to treat AMD, they managed to suppress vessel proliferation and migration, and to restore tissue morphology.
“By printing cells, we’re facilitating the exchange of cellular cues that are necessary for normal outer blood-retina barrier anatomy,” Bharti explained. “For example, presence of RPE cells induces gene expression changes in fibroblasts that contribute to the formation of Bruch’s membrane – something that was suggested many years ago but wasn’t proven until our model.”
“Our collaborative efforts have resulted in very relevant retina tissue models of degenerative eye diseases. Such tissue models have many potential uses in translational applications, including therapeutics development,” concluded co-author Marc Ferrer, the director of the 3D Tissue Bioprinting Laboratory at NIH’s National Center for Advancing Translational Sciences.
The study is published in the journal Nature Methods.
By Andrei Ionescu, Earth.com Staff Writer
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