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Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions.
Stem Cells Transl Med. 2020 03; 9(3):364-376.SC

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.

Authors+Show Affiliations

Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut.Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut.The New York Stem Cell Foundation (NYSCF) Research Institute, New York, New York.The New York Stem Cell Foundation (NYSCF) Research Institute, New York, New York.The New York Stem Cell Foundation (NYSCF) Research Institute, New York, New York.Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut. Department of Surgery, Yale University School of Medicine, New Haven, Connecticut.Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut.Department of Ophthalmology and Visual Science, Yale University School of Medicine, New Haven, Connecticut.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

31840941

Citation

Gong, Jie, et al. "Stem Cell-derived Retinal Pigment Epithelium From Patients With Age-related Macular Degeneration Exhibit Reduced Metabolism and Matrix Interactions." Stem Cells Translational Medicine, vol. 9, no. 3, 2020, pp. 364-376.
Gong J, Cai H, NYSCF Global Stem Cell Array Team, et al. Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions. Stem Cells Transl Med. 2020;9(3):364-376.
Gong, J., Cai, H., Noggle, S., Paull, D., Rizzolo, L. J., Del Priore, L. V., & Fields, M. A. (2020). Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions. Stem Cells Translational Medicine, 9(3), 364-376. https://doi.org/10.1002/sctm.19-0321
Gong J, et al. Stem Cell-derived Retinal Pigment Epithelium From Patients With Age-related Macular Degeneration Exhibit Reduced Metabolism and Matrix Interactions. Stem Cells Transl Med. 2020;9(3):364-376. PubMed PMID: 31840941.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Stem cell-derived retinal pigment epithelium from patients with age-related macular degeneration exhibit reduced metabolism and matrix interactions. AU - Gong,Jie, AU - Cai,Hui, AU - ,, AU - Noggle,Scott, AU - Paull,Daniel, AU - Rizzolo,Lawrence J, AU - Del Priore,Lucian V, AU - Fields,Mark A, Y1 - 2019/12/16/ PY - 2019/09/25/received PY - 2019/11/25/accepted PY - 2019/12/17/pubmed PY - 2021/7/23/medline PY - 2019/12/17/entrez KW - Bruch's membrane KW - age-related macular degeneration KW - aging KW - induced pluripotent stem cells KW - nonenzymatic nitration KW - retinal pigment epithelium SP - 364 EP - 376 JF - Stem cells translational medicine JO - Stem Cells Transl Med VL - 9 IS - 3 N2 - 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. SN - 2157-6580 UR - https://www.unboundmedicine.com/medline/citation/31840941/Stem_cell_derived_retinal_pigment_epithelium_from_patients_with_age_related_macular_degeneration_exhibit_reduced_metabolism_and_matrix_interactions_ L2 - https://doi.org/10.1002/sctm.19-0321 DB - PRIME DP - Unbound Medicine ER -