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iPSC-derived ITGA6-positive cells restore aqueous humor outflow in glaucoma eyes

Author

Listed:
  • Pengchao Feng

    (Qingdao University)

  • Chen Yu

    (Duke University School of Medicine)

  • Xiaoyan Zhang

    (Qingdao University)

  • Bin Xu

    (Ocean University of China)

  • Shen Wu

    (Henan Academy of Innovations in Medical Science
    Beijing Ophthalmology & Visual Sciences Key Laboratory
    Capital Medical University)

  • Chen Xin

    (Beijing Ophthalmology & Visual Sciences Key Laboratory)

  • Sejiro Littleton

    (Duke University School of Medicine
    Duke University School of Medicine)

  • Jie Kang

    (Ocean University of China)

  • Xiangji Wang

    (Qingdao University)

  • Shaoshuai Liang

    (Ltd.)

  • Susu Chen

    (Qingdao University)

  • Wenyan Wang

    (Qingdao University)

  • Yanan Wang

    (Qingdao University)

  • Zhixin Yuan

    (Ltd.)

  • Gaiping Xi

    (Qingdao University)

  • Xinhui Xing

    (Qingdao University)

  • Xinyu Ge

    (Qingdao University)

  • Zhishang Chang

    (Qingdao University)

  • Jinshan Tan

    (Qingdao University)

  • Jingxue Zhang

    (Henan Academy of Innovations in Medical Science
    Beijing Ophthalmology & Visual Sciences Key Laboratory
    Capital Medical University)

  • Bingqiang Zhang

    (Ltd.)

  • Qilong Cao

    (Ltd.
    Yangtze Delta Region Institute of Tsinghua University)

  • Wenhua Xu

    (Qingdao University)

  • Markus H. Kuehn

    (University of Iowa
    Iowa City Veterans Affairs Medical Center)

  • Ningli Wang

    (Henan Academy of Innovations in Medical Science
    Beijing Ophthalmology & Visual Sciences Key Laboratory
    Capital Medical University
    Capital Medical University)

  • Wei Zhu

    (Qingdao University)

Abstract

Decreased trabecular meshwork (TM) cellularity is a critical pathogenic cause of primary open-angle glaucoma, yet therapies to regenerate the decellularized TM are very limited. Induced pluripotent stem cell-derived TM-like cells (iPSC-TM) can efficiently restore aqueous humor outflow. Here, we conducted a multi-modal RNA sequencing analysis to characterize the molecular mechanisms underlying TM regeneration. Our clustering analysis identified a group of iPSC-derived alpha6 integrin-positive (iPSC-ITGA6+) cells with a distinct transcriptome that wasn’t observed in primary TM (pTM) cells. These iPSC-ITGA6+ cells not only stimulate pTM proliferation but also facilitate the repopulation of the TM and Schlemm’s canal in glaucoma, with a much higher efficiency than other iPSC-TM subtypes. Interaction with iPSC-ITGA6+ cells is characterized by the proliferation and rejuvenation of endogenous pTM cells, primarily through the transcription of long non-coding RNA nuclear paraspeckle assembly transcript1 and the abundance of paraspeckles within iPSC-ITGA6+ cells. Enhancing paraspeckle assembly by MEN β-associated RNA promotes the rejuvenation and proliferation of pTM, suggesting a novel and promising approach for TM regeneration.

Suggested Citation

  • Pengchao Feng & Chen Yu & Xiaoyan Zhang & Bin Xu & Shen Wu & Chen Xin & Sejiro Littleton & Jie Kang & Xiangji Wang & Shaoshuai Liang & Susu Chen & Wenyan Wang & Yanan Wang & Zhixin Yuan & Gaiping Xi &, 2025. "iPSC-derived ITGA6-positive cells restore aqueous humor outflow in glaucoma eyes," Nature Communications, Nature, vol. 16(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-65475-8
    DOI: 10.1038/s41467-025-65475-8
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    References listed on IDEAS

    as
    1. Ali Doğa Yücel & Vadim N. Gladyshev, 2024. "The long and winding road of reprogramming-induced rejuvenation," Nature Communications, Nature, vol. 15(1), pages 1-9, December.
    2. Benjamin R. Thomson & Pan Liu & Tuncer Onay & Jing Du & Stuart W. Tompson & Sol Misener & Raj R. Purohit & Terri L. Young & Jing Jin & Susan E. Quaggin, 2021. "Cellular crosstalk regulates the aqueous humor outflow pathway and provides new targets for glaucoma therapies," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    3. Andrew R. Hamel & Wenjun Yan & John M. Rouhana & Aboozar Monovarfeshani & Xinyi Jiang & Puja A. Mehta & Jayshree Advani & Yuyang Luo & Qingnan Liang & Skanda Rajasundaram & Arushi Shrivastava & Kather, 2024. "Integrating genetic regulation and single-cell expression with GWAS prioritizes causal genes and cell types for glaucoma," Nature Communications, Nature, vol. 15(1), pages 1-25, December.
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