Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy
Introduction: Fuchs endothelial corneal dystrophy (FECD) is the leading cause of corneal blindness in developed countries. Corneal endothelial cells in FECD are susceptive to oxidative stress, leading to mitochondrial dysfunction and cell death. Oxidative stress causes many forms of cell death inclu...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-12-01
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| Series: | Regenerative Therapy |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2352320423001062 |
| _version_ | 1827630307111600128 |
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| author | Saki Sakakura Emi Inagaki Tomoko Sayano Risa Yamazaki Noemi Fusaki Shin Hatou Masatoshi Hirayama Kazuo Tsubota Kazuno Negishi Hideyuki Okano Shigeto Shimmura |
| author_facet | Saki Sakakura Emi Inagaki Tomoko Sayano Risa Yamazaki Noemi Fusaki Shin Hatou Masatoshi Hirayama Kazuo Tsubota Kazuno Negishi Hideyuki Okano Shigeto Shimmura |
| author_sort | Saki Sakakura |
| collection | DOAJ |
| description | Introduction: Fuchs endothelial corneal dystrophy (FECD) is the leading cause of corneal blindness in developed countries. Corneal endothelial cells in FECD are susceptive to oxidative stress, leading to mitochondrial dysfunction and cell death. Oxidative stress causes many forms of cell death including parthanatos, which is characterized by translocation of apoptosis-inducing factor (AIF) to the nucleus with upregulation of poly (ADP-ribose) polymerase 1 (PARP-1) and poly (ADP-ribose) (PAR). Although cell death is an important aspect of FECD, previous reports have often analyzed immortalized cell lines, making the evaluation of cell death difficult. Therefore, we established a new in vitro FECD model to evaluate the pathophysiology of FECD. Methods: Corneal endothelial cells were derived from disease-specific induced pluripotent stem cells (iPSCs). Hydrogen peroxide (H2O2) was used as a source for oxidative stress to mimic the pathophysiology of FECD. We investigated the responses to oxidative stress and the involvement of parthanatos in FECD-corneal endothelial cells. Results: Cell death ratio and oxidative stress level were upregulated in FECD with H2O2 treatment compared with non-FECD control, indicating the vulnerability of oxidative stress in FECD. We also found that intracellular PAR, as well as PARP-1 and AIF in the nucleus were upregulated in FECD. Furthermore, PARP inhibition, but not pan-caspase inhibition, rescued cell death, DNA double-strand breaks, mitochondrial membrane potential depolarization and energy depletion, suggesting that cell death was mainly due to parthanatos. Conclusions: We report that parthanatos may be involved in the pathophysiology of FECD and targeting this cell death pathway may be a potential therapeutic approach for FECD. |
| first_indexed | 2024-03-09T14:04:54Z |
| format | Article |
| id | doaj.art-7a365db3a838401b9291b1fd913b44dd |
| institution | Directory Open Access Journal |
| issn | 2352-3204 |
| language | English |
| last_indexed | 2024-03-09T14:04:54Z |
| publishDate | 2023-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Regenerative Therapy |
| spelling | doaj.art-7a365db3a838401b9291b1fd913b44dd2023-11-30T05:07:56ZengElsevierRegenerative Therapy2352-32042023-12-0124592601Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophySaki Sakakura0Emi Inagaki1Tomoko Sayano2Risa Yamazaki3Noemi Fusaki4Shin Hatou5Masatoshi Hirayama6Kazuo Tsubota7Kazuno Negishi8Hideyuki Okano9Shigeto Shimmura10Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Japan Society for the Promotion of Science, 5-3-1 Kojimachi, Chiyoda, Tokyo 102-0083, Japan; Corresponding author. Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Cellusion Inc. 8-6 Nihonbashi-Kobunacho, Chuo-ku, Tokyo 103-0024, JapanDepartment of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanUniversity of Tokyo Pandemic Preparedness, Infection and Advanced Research Center, 4-6-1 Shirokanedai, Minato, Tokyo 108-8639, Japan; Corresponding author.Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Cellusion Inc. 8-6 Nihonbashi-Kobunacho, Chuo-ku, Tokyo 103-0024, JapanDepartment of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Physiology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, JapanDepartment of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan; Department of Clinical Regenerative Medicine, Fujita Medical Innovation Center, Fujita Health University, Haneda Innovation City Zone A, 1-1-4, Hanedakuko, Ota-ku, Tokyo 144-0041, Japan; Corresponding author. Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160-8582, Japan.Introduction: Fuchs endothelial corneal dystrophy (FECD) is the leading cause of corneal blindness in developed countries. Corneal endothelial cells in FECD are susceptive to oxidative stress, leading to mitochondrial dysfunction and cell death. Oxidative stress causes many forms of cell death including parthanatos, which is characterized by translocation of apoptosis-inducing factor (AIF) to the nucleus with upregulation of poly (ADP-ribose) polymerase 1 (PARP-1) and poly (ADP-ribose) (PAR). Although cell death is an important aspect of FECD, previous reports have often analyzed immortalized cell lines, making the evaluation of cell death difficult. Therefore, we established a new in vitro FECD model to evaluate the pathophysiology of FECD. Methods: Corneal endothelial cells were derived from disease-specific induced pluripotent stem cells (iPSCs). Hydrogen peroxide (H2O2) was used as a source for oxidative stress to mimic the pathophysiology of FECD. We investigated the responses to oxidative stress and the involvement of parthanatos in FECD-corneal endothelial cells. Results: Cell death ratio and oxidative stress level were upregulated in FECD with H2O2 treatment compared with non-FECD control, indicating the vulnerability of oxidative stress in FECD. We also found that intracellular PAR, as well as PARP-1 and AIF in the nucleus were upregulated in FECD. Furthermore, PARP inhibition, but not pan-caspase inhibition, rescued cell death, DNA double-strand breaks, mitochondrial membrane potential depolarization and energy depletion, suggesting that cell death was mainly due to parthanatos. Conclusions: We report that parthanatos may be involved in the pathophysiology of FECD and targeting this cell death pathway may be a potential therapeutic approach for FECD.http://www.sciencedirect.com/science/article/pii/S2352320423001062Cell deathFuchs' endothelial corneal dystrophyInduced pluripotent stem cellsOxidative stressParthanatosMitochondria |
| spellingShingle | Saki Sakakura Emi Inagaki Tomoko Sayano Risa Yamazaki Noemi Fusaki Shin Hatou Masatoshi Hirayama Kazuo Tsubota Kazuno Negishi Hideyuki Okano Shigeto Shimmura Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy Regenerative Therapy Cell death Fuchs' endothelial corneal dystrophy Induced pluripotent stem cells Oxidative stress Parthanatos Mitochondria |
| title | Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy |
| title_full | Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy |
| title_fullStr | Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy |
| title_full_unstemmed | Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy |
| title_short | Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy |
| title_sort | non apoptotic regulated cell death in fuchs endothelial corneal dystrophy |
| topic | Cell death Fuchs' endothelial corneal dystrophy Induced pluripotent stem cells Oxidative stress Parthanatos Mitochondria |
| url | http://www.sciencedirect.com/science/article/pii/S2352320423001062 |
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