title: The generation of induced pluripotent stem cells for macular degeneration as a drug screening platform: identification of curcumin as a protective agent for retinal pigment epithelial cells against oxidative stress.
abstract: Age-related macular degeneration (AMD) is one retinal aging process that may lead to irreversible vision loss in the elderly. Its pathogenesis remains unclear, but oxidative stress inducing retinal pigment epithelial (RPE) cells damage is perhaps responsible for the aging sequence of retina and may play an important role in macular degeneration. In this study, we have reprogrammed T cells from patients with dry type AMD into induced pluripotent stem cells (iPSCs) via integration-free episomal vectors and differentiated them into RPE cells that were used as an expandable platform for investigating pathogenesis of the AMD and in-vitro drug screening. These patient-derived RPEs with the AMD-associated background (AMD-RPEs) exhibited reduced antioxidant ability, compared with normal RPE cells. Among several screened candidate drugs, curcumin caused most significant reduction of ROS in AMD-RPEs. Pre-treatment of curcumin protected these AMD-RPEs from H2O2-induced cell death and also increased the cytoprotective effect against the oxidative stress of H2O2 through the reduction of ROS levels. In addition, curcumin with its versatile activities modulated the expression of many oxidative stress-regulating genes such as PDGF, VEGF, IGFBP-2, HO1, SOD2, and GPX1. Our findings indicated that the RPE cells derived from AMD patients have decreased antioxidative defense, making RPE cells more susceptible to oxidative damage and thereby leading to AMD formation. Curcumin represented an ideal drug that can effectively restore the neuronal functions in AMD patient-derived RPE cells, rendering this drug an effective option for macular degeneration therapy and an agent against aging-associated oxidative stress.
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; School of Medicine, Institute of Pharmacology, National Yang-Ming University Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan.
authors.forename: Yun-Ching
authors.initials: YC
authors.lastname: Chang
authors.affiliation: Graduate Institute of Cancer Biology, China Medical University Taichung, Taiwan ; Center for Molecular Medicine, China Medical University Hospital Taichung, Taiwan.
authors.forename: Wei-Chao
authors.initials: WC
authors.lastname: Chang
authors.affiliation: Division of Ophthalmology, National Yang-Ming University Hospital I-Lan, Taiwan ; School of Medicine, Institute of Clinical Medicine, National Yang-Ming University Taipei, Taiwan.
authors.forename: Kuo-Hsuan
authors.initials: KH
authors.lastname: Hung
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan.
authors.forename: Der-Ming
authors.initials: DM
authors.lastname: Yang
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; School of Medicine, Institute of Pharmacology, National Yang-Ming University Taipei, Taiwan.
authors.forename: Yung-Hsin
authors.initials: YH
authors.lastname: Cheng
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan.
authors.forename: Yi-Wen
authors.initials: YW
authors.lastname: Liao
authors.affiliation: Department of Ophthalmology, Taipei City Hospital Taipei, Taiwan.
authors.forename: Lin-Chung
authors.initials: LC
authors.lastname: Woung
authors.affiliation: Department of Ophthalmology, Taipei City Hospital Taipei, Taiwan.
authors.forename: Ching-Yao
authors.initials: CY
authors.lastname: Tsai
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan.
authors.forename: Chih-Chien
authors.initials: CC
authors.lastname: Hsu
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan.
authors.forename: Tai-Chi
authors.initials: TC
authors.lastname: Lin
authors.affiliation: Department of Ophthalmology, Cheng-Hsin Hospital Taipei, Taiwan.
authors.forename: Jorn-Hon
authors.initials: JH
authors.lastname: Liu
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; School of Medicine, Institute of Pharmacology, National Yang-Ming University Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan ; School of Medicine, Institute of Clinical Medicine, National Yang-Ming University Taipei, Taiwan.
authors.forename: Shih-Hwa
authors.initials: SH
authors.lastname: Chiou
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; Department of Ophthalmology, Shin Kong Wu Ho-Su Memorial Hospital and Fu Jen Catholic University Taipei, Taiwan.
authors.forename: Chi-Hsien
authors.initials: CH
authors.lastname: Peng
authors.affiliation: Department of Medical Research and Education, Taipei Veterans General Hospital Taipei, Taiwan ; Department of Ophthalmology, Taipei Veterans General Hospital Taipei, Taiwan.
authors.forename: Shih-Jen
authors.initials: SJ
authors.lastname: Chen
keywords: age-related macular degeneration; antioxidant; curcumin; oxidative stress; patient-specific induced pluripotent stem cells; retinal pigment epithelial