Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy

Saki Sakakura, Emi Inagaki, Tomoko Sayano, Risa Yamazaki, Noemi Fusaki, Shin Hatou, Masatoshi Hirayama, Kazuo Tsubota, Kazuno Negishi, Hideyuki Okano, Shigeto Shimmura

研究成果: ジャーナルへの寄稿学術論文査読

1 被引用数 (Scopus)

抄録

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.

本文言語英語
ページ(範囲)592-601
ページ数10
ジャーナルRegenerative Therapy
24
DOI
出版ステータス出版済み - 12-2023

All Science Journal Classification (ASJC) codes

  • 生体材料
  • 生体医工学
  • 発生生物学

フィンガープリント

「Non-apoptotic regulated cell death in Fuchs endothelial corneal dystrophy」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル