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

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

doi:10.1016/j.stem.2021.02.006

Cited by 38 publications

(46 citation statements)

References 82 publications

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“…This limitation can be overcome by reprogramming somatic cells from affected patients into patient-specific induced pluripotent stem cells (iPSCs) 28 , 29 and subsequently differentiating them into homogenous RPE cultures for downstream disease modeling. iPSC-derived RPE cells have been widely used to demonstrate disease phenotypes and elucidation of disease mechanisms such as those observed in macular dystrophies 30 and in degenerative diseases including AMD 31 – 38 . Patient iPSC-derived cells, including RPE cells, can also be subjected to single-cell RNA-sequencing (scRNA-seq) to precisely characterize individual cells based on their unique transcriptional signature, identify subpopulations of cells within a cell culture and examine rare populations that would be missed using bulk RNA-seq, given its narrower resolution 39 – 42 .…”

Section: Introductionmentioning

confidence: 99%

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

et al. 2022

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There are currently no treatments for geographic atrophy, the advanced form of age-related macular degeneration. Hence, innovative studies are needed to model this condition and prevent or delay its progression. Induced pluripotent stem cells generated from patients with geographic atrophy and healthy individuals were differentiated to retinal pigment epithelium. Integrating transcriptional profiles of 127,659 retinal pigment epithelium cells generated from 43 individuals with geographic atrophy and 36 controls with genotype data, we identify 445 expression quantitative trait loci in cis that are asssociated with disease status and specific to retinal pigment epithelium subpopulations. Transcriptomics and proteomics approaches identify molecular pathways significantly upregulated in geographic atrophy, including in mitochondrial functions, metabolic pathways and extracellular cellular matrix reorganization. Five significant protein quantitative trait loci that regulate protein expression in the retinal pigment epithelium and in geographic atrophy are identified - two of which share variants with cis- expression quantitative trait loci, including proteins involved in mitochondrial biology and neurodegeneration. Investigation of mitochondrial metabolism confirms mitochondrial dysfunction as a core constitutive difference of the retinal pigment epithelium from patients with geographic atrophy. This study uncovers important differences in retinal pigment epithelium homeostasis associated with geographic atrophy.

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Section: Introductionmentioning

confidence: 99%

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

et al. 2022

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“…Recent breakthroughs have overcome the frustrations of past attempts and have already identified potential therapeutic targets. 84 , 86 , 87 , 102 These novel data support continued exploration of RPE-choroid co-cultures by in vivo testing to determine their potential as a tissue-replacement strategy. Further development of these models should also provide a platform to test potential therapeutic agents before committing to expensive animal studies.…”

Section: Discussionmentioning

confidence: 64%

“…A more direct interaction was established between RPE and endothelial cells by using a hydrogel as a scaffold. 86 Human iPSC were used to derive RPE, endothelial cells, and mesenchymal stem cells (MSC). Variations of the following basic culture system were examined.…”

Section: Co-cultures To Study Interactions Of the Rpe With Neighborin...mentioning

confidence: 99%

Retinal Cell Transplantation, Biomaterials, and In Vitro Models for Developing Next-generation Therapies of Age-related Macular Degeneration

Rizzolo

Nasonkin²,

Adelman

2022

Stem Cells Translational Medicine

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Retinal pigment epithelium (RPE) cells grown on a scaffold, an RPE patch, have potential to ameliorate visual impairment in a limited number of retinal degenerative conditions. This tissue-replacement therapy is suited for age-related macular degeneration (AMD), and related diseases. RPE cells must be transplanted before the disease reaches a point of no return, represented by the loss of photoreceptors. Photoreceptors are specialized, terminally differentiated neurosensory cells that must interact with RPE’s apical processes to be functional. Human photoreceptors are not known to regenerate. On the RPE’s basal side, the RPE transplant must induce the reformation of the choriocapillaris, thereby re-establishing the outer blood-retinal barrier. Because the scaffold is positioned between the RPE and choriocapillaris, it should ideally degrade and be replaced by the natural extracellular matrix that separates these tissues. Besides biodegradable, the scaffolds need to be nontoxic, thin enough to not affect the focal length of the eye, strong enough to survive the transplant procedure, yet flexible enough to conform to the curvature of the retina. The challenge is patients with progressing AMD treasure their remaining vision and fear that a risky surgical procedure will further degrade their vision. Accordingly, clinical trials only treat eyes with severe impairment that have few photoreceptors to interact with the transplanted patch. Although safety has been demonstrated, the cell-replacement mechanism and efficacy remain difficult to validate. This review covers the structure of the retina, the pathology of AMD, the limitations of cell therapy approaches, and the recent progress in developing retinal therapies using biomaterials.

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“…In this issue of Cell Stem Cell, Manian et al elegantly reconstructed an iPSCderived three-dimensional (3D) tissue from one neuroectoderm and two mesodermal lineages (Manian et al, 2021). Their advanced 3D cell culture model is a unique platform to investigate RPErelated disease pathologies and the human RPE-CC complex.…”

mentioning

confidence: 99%

“…In order to demonstrate their enhanced disease modeling, Manian et al harvested fibroblasts from normal donors and patients with tissue inhibitor of metallopro-teinases 3 (TIMP3)-related Sorsby Fundus Dystrophy (SFD) (Figure 1) and used these to generate iPSC-derived mesenchyme, ECs, and RPE (Manian et al, 2021). Using a matrix metalloproteinase (MMP)degradable hydrogel, the authors encapsulated the ECs between a layer of mesenchyme and a layer of RPE, closely emulating the architecture of the oBRB.…”

mentioning

confidence: 99%

Overcoming translational barriers in modeling macular degenerations

2021

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

Cited by 38 publications

References 82 publications

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Transcriptomic and proteomic retinal pigment epithelium signatures of age-related macular degeneration

Retinal Cell Transplantation, Biomaterials, and In Vitro Models for Developing Next-generation Therapies of Age-related Macular Degeneration

Overcoming translational barriers in modeling macular degenerations

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