Retinal drusen formation is not only a clinical hallmark for the development of age-related macular degeneration (AMD) but also for other disorders, such as Alzheimer's disease and renal diseases. The initiation and growth of drusen is poorly and systemic side" of drusen. 6.2. Nineteen drusen proteins out of 89 were not assigned. 6.3. Blood proteins are an important source of drusen proteins. 7. Drusen and hydroxyapatite. 8. Drusen and plaques: age-related macular degeneration and atherosclerosis. 8.1. Clinical and epidemiological studies. 8.2. Histological and pathobiological similarities. 8.3. Genetics and molecular biology. 9. Future directions and conclusions.

Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retinabarrier (oBRB) formed by Retinal pigment epithelium (RPE), Bruch's membrane, and choriocapillaris. The mechanism of AMD initiation and progression remain poorly understood due to the lack of physiologically relevant oBRB models. We engineered a native-like 3D-oBRB tissue by bioprinting endothelial cells, pericytes, and fibroblasts on the basal side of a biodegradable scaffold and establishing an RPE monolayer on top. In this 3D-oBRB, a fully-polarized RPE monolayer with apical processes and basal infoldings provides barrier resistance, induces fenestration and choroid-specific gene expression in the choriocapillaris, and supports the formation of a Bruch's-like membrane that allows tissue integration in rat eyes. Complement activation in the 3D-oBRB triggers dry-AMD phenotypes (including subRPE drusen and choriocapillaris degeneration), and hypoxia activated HIF-α induces wet-AMD phenotypes (choriocapillaris neovascularization). Anti-VEGF drug treatment suppresses neovascularizationvalidating this model for clinical translation and drug discovery.

In age-related macular degeneration (AMD) the retinal pigment epithelium (RPE) deteriorates, leading to photoreceptor decay and severe vision loss. New therapeutic strategies aim at RPE replacement by transplantation of pluripotent stem cell (PSC)-derived RPE. Several protocols to generate RPE have been developed where appearance of pigmentation is commonly used as indicator of RPE differentiation and maturation. It is, however, unclear how different pigmentation stages reflect developmental stages and functionality of PSC-derived RPE cells. We generated human embryonic stem cell-derived RPE (hESC-RPE) cells and investigated their gene expression profiles at early pigmentation (EP) and late pigmentation (LP) stages. In addition, we compared the hESC-RPE samples with human endogenous RPE. We used a common reference design microarray (44 K). Our analysis showed that maturing hESC-RPE, upon acquiring pigmentation, expresses markers specific for human RPE. Interestingly, our analysis revealed that EP and LP hESC-RPE do not differ much in gene expression. Our data further showed that pigmented hESC-RPE has a significant lower expression than human endogenous RPE in the visual cycle and oxidative stress pathways. In contrast, we observed a significantly higher expression of pathways related to the process adhesion-to-polarity model that is typical of developing epithelial cells. We conclude that, in vitro, the first appearance of pigmentation hallmarks differentiated RPE. However, further increase in pigmentation does not result in much significant gene expression changes and does not add important RPE functionalities. Consequently, our results suggest that the time span for obtaining differentiated hESC-RPE cells, that are suitable for transplantation, may be greatly reduced.Electronic supplementary materialThe online version of this article (doi:10.1007/s12015-017-9754-0) contains supplementary material, which is available to authorized users.