Cell to cell interaction leading to metabolic interference trigger the aggravated degeneration of human corneal endothelial cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 20H03844
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 56060:Ophthalmology-related
• Research Institution: Kyoto Prefectural University of Medicine
• Principal Investigator: Kinoshita Shigeru 京都府立医科大学, 医学(系)研究科(研究院), 教授 (30116024)
• Co-Investigator(Kenkyū-buntansha): 上野 盛夫 京都府立医科大学, 医学(系)研究科(研究院), 講師 (40426531) ; 羽室 淳爾 京都府立医科大学, 医学(系)研究科(研究院), 客員教授 (80536095)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 角膜移植 / 再生医療 / 細胞外小胞体 / マイクロRNA / 細胞競合 / 水泡性角膜症

Outline of Final Research Achievements

The miRs in aueous humors (AqH) were classified into 2 groups: the expression in 1 group was either significantly reduced in neonate-derived tissues or remained almost constant. The miR-34a and -29 families were in the former group, whereas miR-184 and -24-3p in the latter. Secretions of VEGF, IL- 6 and MCP-1 were all repressed in both mature CD44-/dull and degenerated CD44+++human corneal endothelial cells(hCEC), transfected with an miR-184 mimic. The metabolites, 3-hydroxyisobutyric acid (HIB)and 2-aminobutyric acid (AB) were decreased in the AqH of BK patients. The Lasso analysis identified the interplay between miR-34a-5p and HIB and between miR-24-3p and AB. HIB upregulated the cellular miR-34a expression, mitochondrial membrane potential and release of EV miR-184 in de-differentiated cultured hCECs. Metabolites and miRs in AqH may synchronize in ensuring the integrity of the hHCE tissues to maintain efficient dehydration from the stroma.

Free Research Field

眼科学、細胞生物学

Academic Significance and Societal Importance of the Research Achievements

本課題の達成は広く細胞医療・移植医療に大きな意義を有する。細胞変性の係る加齢性疾患病態の細胞機構を明らかにし革新的創薬概念に結び付く。その斬新性と独創性ならびに角膜内皮機能不全患者病態に直結する意義は高く評価されている。細胞間干渉がEVに包含されるmiRや代謝産物に担われる可能性への切込みも他細胞領域を含め独創的である。新しい学術領域を拓く。角膜移植同様、細胞品質の劣る細胞注入再生医療でも注入後3－5年経過すると角膜内皮細胞密度は次第に低下する。慢性的な角膜内細胞密度の低下がいかなる機構で起こるかについては、本研究により細胞間代謝干渉による細胞変性の増幅と病態増悪の新概念を提唱するに至った。