Metabolic Plasticity in Cell State Homeostasis and Differentiation of Cultured Human Corneal Endothelial Cells as A New Target for Drug Development

• Project/Area Number: 26670759
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Ophthalmology
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: SOTOZONO CHIE 京都府立医科大学, 医学(系)研究科(研究院), 教授 (30216585)
• Co-Investigator(Kenkyū-buntansha): 羽室 淳爾 京都府立医科大学, 医学(系)研究科(研究院), 特任教授 (80536095)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2016: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 角膜内皮細胞 / エネルギー代謝応答 / 解糖系 / ミトコンドリア / 代謝リモデリング / miRNA / 細胞相転移 / ヒト角膜内皮細胞 / 相転移 / CD44 / SASP / エネルギー代謝経路 / 細胞亜集団 / 培養ヒト角膜内皮細胞 / EMT / メタボローム解析 / 解糖系エネルギー代謝

Outline of Final Research Achievements

In this　study, we found the way, using the culture supernatants, to　discrimiーnate SPs in cHCECs in terms of their secretory metabolites, and found that the CST SPs exhibited the disposition to the anaerobic glycolysis instead of mitoc-hondria-dependent OXPHOS. The study on the secretory metabolites assigned the cHCEC SPs distinct in the expression levels of surface CD44 antigen. Transition from oxidative metabolism into glycolysis is a prerequisite for reprogramming to the pluripotent state. Conversely, redirection of pluripotency into defined lineages requires　mito- chondrial biogenesis and maturation of efficient oxidative energy generati- on.The reduction of glycolysis might be triggered by downregulation of the cMyc pathway.Our novel findings provide evidence of a possible link between metabo-lic regulation in the corneal endothelium and the development of more effective targeted therapies to treat patients with bullous keratopathy, including FECD.

Research Products

• [Journal Article] Cell Homogeneity Indispensable for Regenerative Medicine by Cultured Human Corneal Endothelial Cells. (2016)
  • Author(s): Hamuro J, Toda M, Asada K, Hiraga A, Schlötzer-Schrehardt U, Montoya M,
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 57 Issue: 11 Pages: 4749-4761
  • DOI: 10.1167/iovs.16-19770
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] 8.Metabolic Plasticity in Cell State Homeostasis and Differentiation of Cultured Human Corneal Endothelial Cells. (2016)
  • Author(s): Hamuro J, Ueno M, Asada K, Toda M, Montoya M, Sotozono C, Kinoshita S.
  • Journal Title: Invest Ophthalmol Vis Sci. Volume: 57 Issue: 10 Pages: 4452-4463
  • DOI: 10.1167/iovs.16-19807
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Concomitant Evaluation of a Panel of Exosome Proteins and MiRs for Qualification of Cultured Human Corneal Endothelial Cells (2016)
  • Author(s): Morio Ueno, Kazuko Asada, Munetoyo Toda, Kazue Nagata, Chie Sotozono, Nobuyoshi Kosaka, Takahiro Ochiya, Shigeru Kinoshita, Junji Hamuro
  • Organizer: IISEV2016
  • Place of Presentation: Rotterdam, Netherland
  • Year and Date: 2016-05-03
  • Int'l Joint Research
• [Presentation] The role of dysregulated expression of miRs in pathogenesis of BK and FECD (2016)
  • Author(s): Kazuko Asada, Morio Ueno, Munetoyo Toda, Asako Hiraga, Monty Montoya, Chie Sotozono, Shigeru Kinoshita
  • Organizer: 87th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology）
  • Place of Presentation: シアトル市、USA
  • Year and Date: 2016-04-30
  • Int'l Joint Research
• [Presentation] 角膜内皮細胞機能不全におけるepigeneticな細胞機能制御 (2016)
  • Author(s): 浅田 和子、上野 盛夫、戸田宗豊、平賀朝子、落谷孝広、外園千恵、木下茂、羽室淳爾
  • Organizer: 日本眼科学会総会
  • Place of Presentation: 仙台市
  • Year and Date: 2016-04-07
• [Presentation] Regulation of mitochondrial respiration under cell culture stress in human corneal endothelial cells (2016)
  • Author(s): Kinoshita S, Ueno M, Asada K, Toda M, Nagata K, Sotozono C, Kosaka N, Ochiya T, Hamuro J
  • Organizer: ARVO 2016 Annual Meeting
  • Place of Presentation: Seattle, WA, USA
  • Int'l Joint Research
• [Presentation] Metabolic plasticity in the cell-state homeostasis and differentiation of cultured human corneal endothelial cells (2016)
  • Author(s): Hamuro J, Ueno M, Asada K, Toda M, Montoya M, Sotozono C, Kinoshita S.
  • Organizer: ARVO 2016 Annual Meeting
  • Place of Presentation: Seattle, WA, USA
  • Int'l Joint Research
• [Presentation] Analysis of cytokines in serum and aqueous humor in patients with bullous keratopathy (2015)
  • Author(s): Morio Ueno, Munetoyo Toda, Asako HIraga, Naomi Tobita, Hiroko Nakagawa, Chie Sotozono, Noriko Koizumi, Naoki Okumura, Kazuko Asada, Junji Hamuro, and Shigeru Kinoshita
  • Organizer: 87th Annual meeting of the ARVO (Association for Research in Vision and Ophthalmology)
  • Place of Presentation: Denver, Colorado, USA
  • Year and Date: 2015-05-06