TY - JOUR
T1 - Bioprinted 3D outer retina barrier uncovers RPE-dependent choroidal phenotype in advanced macular degeneration
AU - Song, Min Jae
AU - Quinn, Russ
AU - Nguyen, Eric
AU - Hampton, Christopher
AU - Sharma, Ruchi
AU - Park, Tea Soon
AU - Koster, C. line
AU - Voss, Ty
AU - Tristan, Carlos
AU - Weber, Claire
AU - Singh, Anju
AU - Dejene, Roba
AU - Bose, Devika
AU - Chen, Yu-Chi
AU - Derr, Paige
AU - Derr, Kristy
AU - Michael, Sam
AU - Barone, Francesca
AU - Chen, Guibin
AU - Boehm, Manfred
AU - Maminishkis, Arvydas
AU - Singec, Ilyas
AU - Ferrer, Marc
AU - Bharti, Kapil
N1 - Funding Information: The authors thank R. Fariss, NEI Biological Imaging Core, M. Abu from NEI histology core for processing the samples for TEM and taking images, D. McGaughey OGVFB, NEI for advice on scRNA-seq data analysis. This work was supported by funds from the NEI Intramural Research Program to K.B., NCATS intramural funds to M.J.S., M.F., and I.S., NHLBI intramural funds to M.B., Department of Defense grant (grant number 11831456) to M.J.S. and K.B., and Cures Acceleration Network program to M.J.S. and M.F. Publisher Copyright: © 2022, This is a U.S. Government work and not under copyright protection in the US; foreign copyright protection may apply.
PY - 2023/1
Y1 - 2023/1
N2 - Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. To this end, we engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) 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 model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch’s-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE–choriocapillaris interactions under healthy and diseased conditions.
AB - Age-related macular degeneration (AMD), a leading cause of blindness, initiates in the outer-blood-retina-barrier (oBRB) formed by the retinal pigment epithelium (RPE), Bruch’s membrane, and choriocapillaris. The mechanisms of AMD initiation and progression remain poorly understood owing to the lack of physiologically relevant human oBRB models. To this end, we engineered a native-like three-dimensional (3D) oBRB tissue (3D-oBRB) 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 model, a fully-polarized RPE monolayer provides barrier resistance, induces choriocapillaris fenestration, and supports the formation of Bruch’s-membrane-like structure by inducing changes in gene expression in cells of the choroid. Complement activation in the 3D-oBRB triggers dry AMD phenotypes (including subRPE lipid-rich deposits called drusen and choriocapillaris degeneration), and HIF-α stabilization or STAT3 overactivation induce choriocapillaris neovascularization and type-I wet AMD phenotype. The 3D-oBRB provides a physiologically relevant model to studying RPE–choriocapillaris interactions under healthy and diseased conditions.
UR - http://www.scopus.com/inward/record.url?scp=85144686535&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41592-022-01701-1
DO - https://doi.org/10.1038/s41592-022-01701-1
M3 - Article
C2 - 36550275
SN - 1548-7091
VL - 20
SP - 149
EP - 161
JO - Nature methods
JF - Nature methods
IS - 1
ER -