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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)846-862.e8
JournalCell Stem Cell
Volume28
Issue number5
DOIs
StatePublished - May 6 2021
Externally publishedYes

Bibliographical note

Funding Information:
This work was supported by a BrightFocus Foundation Macular Degeneration Grant (to R.S.), Cleveland Eye Bank Foundation Grant (B.A-A.), the David Bryant Trust (to R.S.), a Foundation Fighting Blindness Individual Investigator Award (to R.S.), a Knights Templar eye foundation grant (to R.S.), and the Retina Research Foundation and Research to Prevent Blindness (Career Development Award to R.S. and an unrestricted challenge grant to the Department of Ophthalmology at the University of Rochester and the Department of Ophthalmic Research at Cleveland Clinic). This work was also supported by National Institutes of Health grants R01EY028167 (to R.S.), R01EY030183 (to R.S.), R21EY027750 (to D.S.W.B. and R.S.), 5T32ES007026-43 (to J.A.M.), R01NS109427 (to W.L.M.), EY027083 and EY026181 (to B.A.-A.), and P30EY025585 (to the Cleveland Clinic Foundation). Conceptualization and methodology, R.S. D.S.W.B. M.C. and B.A-A.; investigation, K.V.M. C.A.G. S.D. A.A.E. L.W. C.S. W.B. Y.L. and W.D.; visualization, A.K. I.S. M.P.S. W.L.M. M.C. J.A.M. D.S.W.B. and R.S.; formal analysis, K.V.M. C.A.G. S.D. A.A.E. L.W. C.S. W.S, Y.L. Y.S. J.A.M. D.S.W.B. and R.S.; writing ? original draft, K.V.M. M.P.S. D.S.W.B. and R.S.; writing ? review & editing, K.V.M. C.A.G. S.D. A.A.E. L.W. C.S. W.S, Y.L. Y.S. J.A.M. A.K. I.S. M.P.S. W.L.M. B.A-A. D.S.W.B. and R.S.; resources, M.C.; project administration and supervision, R.S. and D.S.W.B.; funding acquisition, R.S. and D.S.W.B. The authors declare no competing interests.

Funding Information:
This work was supported by a BrightFocus Foundation Macular Degeneration Grant (to R.S.), Cleveland Eye Bank Foundation Grant (B.A-A.), the David Bryant Trust (to R.S.), a Foundation Fighting Blindness Individual Investigator Award (to R.S.), a Knights Templar eye foundation grant (to R.S.), and the Retina Research Foundation and Research to Prevent Blindness (Career Development Award to R.S. and an unrestricted challenge grant to the Department of Ophthalmology at the University of Rochester and the Department of Ophthalmic Research at Cleveland Clinic). This work was also supported by National Institutes of Health grants R01EY028167 (to R.S.), R01EY030183 (to R.S.), R21EY027750 (to D.S.W.B. and R.S.), 5T32ES007026-43 (to J.A.M.), R01NS109427 (to W.L.M.), EY027083 and EY026181 (to B.A.-A.), and P30EY025585 (to the Cleveland Clinic Foundation).

Publisher Copyright:
© 2021 Elsevier Inc.

Keywords

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

PubMed: MeSH publication types

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

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