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Altered transcriptome and disease-related phenotype emerge only after fibroblasts harvested from patients with age-related macular degeneration are differentiated into retinal pigment epithelium.
Exp Eye Res. 2021 06; 207:108576.EE

Abstract

We have reported previously that retinal pigment epithelium (RPE) differentiated from induced pluripotent stem cells (iPSC) generated from fibroblasts of patients with age-related macular degeneration (AMD) exhibit a retinal degenerative disease phenotype and a distinct transcriptome compared to age-matched controls. Since the genetic composition of the iPSC and RPE are inherited from fibroblasts, we investigated whether differential behavior was present in the parental fibroblasts and iPSC prior to differentiation of the cell lines into RPE. Principal component analyses revealed significant overlap (essentially no differences) in the transcriptome of fibroblasts between AMD and controls. After reprogramming, there was no significant difference in the transcriptome of iPSC generated from AMD versus normal donors. In contrast, the transcriptome of RPE derived from iPSC segregated into two distinct clusters of AMD-derived cells versus controls. Interestingly, mitochondrial dysfunction in AMD-derived RPE was evident after approximately two months in culture. Moreover, these differences in mitochondrial dysfunction were not evident in the parental fibroblasts and iPSC. This study demonstrates an altered transcriptome and impaired mitochondrial function in RPE derived from AMD patients versus controls, and demonstrates these differences are not present in the original fibroblasts or iPSC. These results suggest that pathology in AMD is triggered upon differentiation of parent cells into RPE. More study of this phenomenon could advance the current understandings of the etiology of AMD and the development of novel therapeutic targets.

Authors+Show Affiliations

Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George St., Suite 8100, New Haven, CT, 06510, USA.Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George St., Suite 8100, New Haven, CT, 06510, USA.The New York Stem Cell Foundation (NYSCF) Research Institute, 619 West 54th St., New York, NY, 10019, USA.The New York Stem Cell Foundation (NYSCF) Research Institute, 619 West 54th St., New York, NY, 10019, USA.The New York Stem Cell Foundation (NYSCF) Research Institute, 619 West 54th St., New York, NY, 10019, USA.Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George St., Suite 8100, New Haven, CT, 06510, USA; Department of Surgery, Yale University School of Medicine, PO Box 208062, New Haven, CT, 06520-8062, USA.Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George St., Suite 8100, New Haven, CT, 06510, USA.Department of Ophthalmology and Visual Science, Yale University School of Medicine, 300 George St., Suite 8100, New Haven, CT, 06510, USA. Electronic address: mark.fields@yale.edu.

Pub Type(s)

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

Language

eng

PubMed ID

33895162

Citation

Cai, Hui, et al. "Altered Transcriptome and Disease-related Phenotype Emerge Only After Fibroblasts Harvested From Patients With Age-related Macular Degeneration Are Differentiated Into Retinal Pigment Epithelium." Experimental Eye Research, vol. 207, 2021, p. 108576.
Cai H, Gong J, NYSCF Global Stem Cell Array Team, et al. Altered transcriptome and disease-related phenotype emerge only after fibroblasts harvested from patients with age-related macular degeneration are differentiated into retinal pigment epithelium. Exp Eye Res. 2021;207:108576.
Cai, H., Gong, J., Noggle, S., Paull, D., Rizzolo, L. J., Del Priore, L. V., & Fields, M. A. (2021). Altered transcriptome and disease-related phenotype emerge only after fibroblasts harvested from patients with age-related macular degeneration are differentiated into retinal pigment epithelium. Experimental Eye Research, 207, 108576. https://doi.org/10.1016/j.exer.2021.108576
Cai H, et al. Altered Transcriptome and Disease-related Phenotype Emerge Only After Fibroblasts Harvested From Patients With Age-related Macular Degeneration Are Differentiated Into Retinal Pigment Epithelium. Exp Eye Res. 2021;207:108576. PubMed PMID: 33895162.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Altered transcriptome and disease-related phenotype emerge only after fibroblasts harvested from patients with age-related macular degeneration are differentiated into retinal pigment epithelium. AU - Cai,Hui, AU - Gong,Jie, AU - ,, AU - Noggle,Scott, AU - Paull,Daniel, AU - Rizzolo,Lawrence J, AU - Del Priore,Lucian V, AU - Fields,Mark A, Y1 - 2021/04/22/ PY - 2020/12/01/received PY - 2021/03/03/revised PY - 2021/04/07/accepted PY - 2021/4/26/pubmed PY - 2021/9/18/medline PY - 2021/4/25/entrez KW - Age-related macular degeneration KW - Differentiation KW - Fibroblast KW - Gene expression KW - Human induced pluripotent stem cells KW - Mitochondria KW - Retinal pigment epithelium KW - Transcriptome SP - 108576 EP - 108576 JF - Experimental eye research JO - Exp Eye Res VL - 207 N2 - We have reported previously that retinal pigment epithelium (RPE) differentiated from induced pluripotent stem cells (iPSC) generated from fibroblasts of patients with age-related macular degeneration (AMD) exhibit a retinal degenerative disease phenotype and a distinct transcriptome compared to age-matched controls. Since the genetic composition of the iPSC and RPE are inherited from fibroblasts, we investigated whether differential behavior was present in the parental fibroblasts and iPSC prior to differentiation of the cell lines into RPE. Principal component analyses revealed significant overlap (essentially no differences) in the transcriptome of fibroblasts between AMD and controls. After reprogramming, there was no significant difference in the transcriptome of iPSC generated from AMD versus normal donors. In contrast, the transcriptome of RPE derived from iPSC segregated into two distinct clusters of AMD-derived cells versus controls. Interestingly, mitochondrial dysfunction in AMD-derived RPE was evident after approximately two months in culture. Moreover, these differences in mitochondrial dysfunction were not evident in the parental fibroblasts and iPSC. This study demonstrates an altered transcriptome and impaired mitochondrial function in RPE derived from AMD patients versus controls, and demonstrates these differences are not present in the original fibroblasts or iPSC. These results suggest that pathology in AMD is triggered upon differentiation of parent cells into RPE. More study of this phenomenon could advance the current understandings of the etiology of AMD and the development of novel therapeutic targets. SN - 1096-0007 UR - https://www.unboundmedicine.com/medline/citation/33895162/Altered_transcriptome_and_disease_related_phenotype_emerge_only_after_fibroblasts_harvested_from_patients_with_age_related_macular_degeneration_are_differentiated_into_retinal_pigment_epithelium_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-4835(21)00141-X DB - PRIME DP - Unbound Medicine ER -