3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration

Kannan V Manian; Chad A Galloway; Sonal Dalvi; Anthony A Emanuel; Jared A Mereness; Whitney Black; Lauren Winschel; Celia Soto; Yiming Li; Yuanhui Song; William DeMaria; Akhilesh Kumar; Igor Slukvin; Michael P Schwartz; William L Murphy; Bela Anand-Apte; Mina Chung; Danielle S W Benoit; Ruchira Singh

doi:10.1016/j.stem.2021.02.006

3D iPSC modeling of the retinal pigment epithelium-choriocapillaris complex identifies factors involved in the pathology of macular degeneration

Cell Stem Cell. 2021 May 6;28(5):846-862.e8. doi: 10.1016/j.stem.2021.02.006. Epub 2021 Mar 29.

Authors

Kannan V Manian¹, Chad A Galloway², Sonal Dalvi¹, Anthony A Emanuel¹, Jared A Mereness³, Whitney Black¹, Lauren Winschel¹, Celia Soto¹, Yiming Li⁴, Yuanhui Song⁴, William DeMaria⁴, Akhilesh Kumar⁵, Igor Slukvin⁶, Michael P Schwartz⁷, William L Murphy⁸, Bela Anand-Apte⁹, Mina Chung¹⁰, Danielle S W Benoit¹¹, Ruchira Singh¹²

Affiliations

¹ Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA.
² Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14620, USA.
³ Department of Biomedical Engineering, Robert B. Goergen Hall, University of Rochester, Rochester, NY 14627, USA; Department of Orthopedics and Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA; Center for Oral Biology, University of Rochester, Rochester, NY 14642, USA; Department of Environmental Medicine, University of Rochester, Rochester, NY 14642 USA.
⁴ Department of Biomedical Engineering, Robert B. Goergen Hall, University of Rochester, Rochester, NY 14627, USA.
⁵ Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA.
⁶ Wisconsin National Primate Research Center, University of Wisconsin, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin School of Medicine and Public Health, Madison, WI 53715, USA.
⁷ NSF Center for Sustainable Nanotechnology, Department of Chemistry, University of Wisconsin, Madison, WI 53706, USA; Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53715, USA.
⁸ Department of Biomedical Engineering, University of Wisconsin, Madison, WI 53715, USA; Department of Orthopedics and Rehabilitation, University of Wisconsin, Madison, WI 53715, USA.
⁹ Department of Ophthalmic Research, Cole Eye Institute and Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
¹⁰ Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA.
¹¹ Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Engineering, Robert B. Goergen Hall, University of Rochester, Rochester, NY 14627, USA; Department of Orthopedics and Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA; Center for Oral Biology, University of Rochester, Rochester, NY 14642, USA; Department of Environmental Medicine, University of Rochester, Rochester, NY 14642 USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA; Materials Science Program, University of Rochester, Rochester, NY 14620, USA; Department of Chemical Engineering, University of Rochester, NY 14620, USA.
¹² Department of Ophthalmology, University of Rochester, Rochester, NY 14620, USA; Department of Biomedical Genetics, University of Rochester, Rochester, NY 14620, USA; Department of Orthopedics and Center for Musculoskeletal Research, University of Rochester, Rochester, NY 14642, USA; Center for Visual Science, University of Rochester, Rochester, NY 14620, USA; UR Stem Cell and Regenerative Medicine Center, Rochester, NY 14620, USA. Electronic address: [email protected].

Abstract

The retinal pigment epithelium (RPE)-choriocapillaris (CC) complex in the eye is compromised in age-related macular degeneration (AMD) and related macular dystrophies (MDs), yet in vitro models of RPE-CC complex that enable investigation of AMD/MD pathophysiology are lacking. By incorporating iPSC-derived cells into a hydrogel-based extracellular matrix, we developed a 3D RPE-CC model that recapitulates key features of both healthy and AMD/MD eyes and provides modular control over RPE and CC layers. Using this 3D RPE-CC model, we demonstrated that both RPE- and mesenchyme-secreted factors are necessary for the formation of fenestrated CC-like vasculature. Our data show that choroidal neovascularization (CNV) and CC atrophy occur in the absence of endothelial cell dysfunction and are not necessarily secondary to drusen deposits underneath RPE cells, and CC atrophy and/or CNV can be initiated systemically by patient serum or locally by mutant RPE-secreted factors. Finally, we identify FGF2 and matrix metalloproteinases as potential therapeutic targets for AMD/MDs.

Keywords: Sorsby's fundus dystrophy; age-related macular degeneration; choriocapillaris; choroidal neovascularization; hydrogel; induced pluripotent stem cell; macular dystrophy; retinal pigment epithelium; tissue engineering.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Choroid
Choroid Diseases*
Humans
Induced Pluripotent Stem Cells*
Macular Degeneration*
Retinal Pigment Epithelium

Abstract

Publication types

MeSH terms

Grants and funding