Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions
Abstract Modeling age‐related macular degeneration (AMD) is challenging, because it is a multifactorial disease. To focus on interactions between the retinal pigment epithelium (RPE) and Bruch's membrane, we generated RPE from AMD patients and used an altered extracellular matrix (ECM) that mod...
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| Format: | Article |
| Language: | English |
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Oxford University Press
2020-03-01
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| Series: | Stem Cells Translational Medicine |
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| Online Access: | https://doi.org/10.1002/sctm.19-0321 |
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| author | Jie Gong Hui Cai NYSCF Global Stem Cell Array Team Scott Noggle Daniel Paull Lawrence J. Rizzolo Lucian V. Del Priore Mark A. Fields |
| author_facet | Jie Gong Hui Cai NYSCF Global Stem Cell Array Team Scott Noggle Daniel Paull Lawrence J. Rizzolo Lucian V. Del Priore Mark A. Fields |
| author_sort | Jie Gong |
| collection | DOAJ |
| description | Abstract Modeling age‐related macular degeneration (AMD) is challenging, because it is a multifactorial disease. To focus on interactions between the retinal pigment epithelium (RPE) and Bruch's membrane, we generated RPE from AMD patients and used an altered extracellular matrix (ECM) that models aged Bruch's membrane. Induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from AMD patients or age‐matched (normal) controls. RPE derived from iPSCs were analyzed by morphology, marker expression, transepithelial electrical resistance (TER), and phagocytosis of rod photoreceptor outer segments. Cell attachment and viability was tested on nitrite‐modified ECM, a typical modification of aged Bruch's membrane. DNA microarrays with hierarchical clustering and analysis of mitochondrial function were used to elucidate possible mechanisms for the observed phenotypes. Differentiated RPE displayed cell‐specific morphology and markers. The TER and phagocytic capacity were similar among iPSC‐derived RPE cultures. However, distinct clusters were found for the transcriptomes of AMD and control iPSC‐derived RPE. AMD‐derived iPSC‐RPE downregulated genes responsible for metabolic‐related pathways and cell attachment. AMD‐derived iPSC‐RPE exhibited reduced mitochondrial respiration and ability to attach and survive on nitrite‐modified ECM. Cells that did attach induced the expression of complement genes. Despite reprogramming, iPSC derived from AMD patients yielded RPE with a transcriptome that is distinct from that of age‐matched controls. When challenged with an AMD‐like modification of Bruch's membrane, AMD‐derived iPSC‐RPE activated the complement immune system. |
| first_indexed | 2024-12-20T15:40:13Z |
| format | Article |
| id | doaj.art-85da29d155e04d769625b2417f5e555c |
| institution | Directory Open Access Journal |
| issn | 2157-6564 2157-6580 |
| language | English |
| last_indexed | 2024-12-20T15:40:13Z |
| publishDate | 2020-03-01 |
| publisher | Oxford University Press |
| record_format | Article |
| series | Stem Cells Translational Medicine |
| spelling | doaj.art-85da29d155e04d769625b2417f5e555c2022-12-21T19:35:14ZengOxford University PressStem Cells Translational Medicine2157-65642157-65802020-03-019336437610.1002/sctm.19-0321Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactionsJie Gong0Hui Cai1NYSCF Global Stem Cell Array Team2Scott Noggle3Daniel Paull4Lawrence J. Rizzolo5Lucian V. Del Priore6Mark A. Fields7Department of Ophthalmology and Visual Science Yale University School of Medicine New Haven ConnecticutDepartment of Ophthalmology and Visual Science Yale University School of Medicine New Haven ConnecticutThe New York Stem Cell Foundation (NYSCF) Research Institute New York New YorkThe New York Stem Cell Foundation (NYSCF) Research Institute New York New YorkThe New York Stem Cell Foundation (NYSCF) Research Institute New York New YorkDepartment of Ophthalmology and Visual Science Yale University School of Medicine New Haven ConnecticutDepartment of Ophthalmology and Visual Science Yale University School of Medicine New Haven ConnecticutDepartment of Ophthalmology and Visual Science Yale University School of Medicine New Haven ConnecticutAbstract Modeling age‐related macular degeneration (AMD) is challenging, because it is a multifactorial disease. To focus on interactions between the retinal pigment epithelium (RPE) and Bruch's membrane, we generated RPE from AMD patients and used an altered extracellular matrix (ECM) that models aged Bruch's membrane. Induced pluripotent stem cells (iPSCs) were generated from fibroblasts isolated from AMD patients or age‐matched (normal) controls. RPE derived from iPSCs were analyzed by morphology, marker expression, transepithelial electrical resistance (TER), and phagocytosis of rod photoreceptor outer segments. Cell attachment and viability was tested on nitrite‐modified ECM, a typical modification of aged Bruch's membrane. DNA microarrays with hierarchical clustering and analysis of mitochondrial function were used to elucidate possible mechanisms for the observed phenotypes. Differentiated RPE displayed cell‐specific morphology and markers. The TER and phagocytic capacity were similar among iPSC‐derived RPE cultures. However, distinct clusters were found for the transcriptomes of AMD and control iPSC‐derived RPE. AMD‐derived iPSC‐RPE downregulated genes responsible for metabolic‐related pathways and cell attachment. AMD‐derived iPSC‐RPE exhibited reduced mitochondrial respiration and ability to attach and survive on nitrite‐modified ECM. Cells that did attach induced the expression of complement genes. Despite reprogramming, iPSC derived from AMD patients yielded RPE with a transcriptome that is distinct from that of age‐matched controls. When challenged with an AMD‐like modification of Bruch's membrane, AMD‐derived iPSC‐RPE activated the complement immune system.https://doi.org/10.1002/sctm.19-0321age‐related macular degenerationagingBruch's membraneinduced pluripotent stem cellsnonenzymatic nitrationretinal pigment epithelium |
| spellingShingle | Jie Gong Hui Cai NYSCF Global Stem Cell Array Team Scott Noggle Daniel Paull Lawrence J. Rizzolo Lucian V. Del Priore Mark A. Fields Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions Stem Cells Translational Medicine age‐related macular degeneration aging Bruch's membrane induced pluripotent stem cells nonenzymatic nitration retinal pigment epithelium |
| title | Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions |
| title_full | Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions |
| title_fullStr | Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions |
| title_full_unstemmed | Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions |
| title_short | Stem cell‐derived retinal pigment epithelium from patients with age‐related macular degeneration exhibit reduced metabolism and matrix interactions |
| title_sort | stem cell derived retinal pigment epithelium from patients with age related macular degeneration exhibit reduced metabolism and matrix interactions |
| topic | age‐related macular degeneration aging Bruch's membrane induced pluripotent stem cells nonenzymatic nitration retinal pigment epithelium |
| url | https://doi.org/10.1002/sctm.19-0321 |
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