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<p>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<sup>+</sup>) cells with a distinct&#xa0;transcriptome that wasn’t observed in primary TM (pTM) cells. These iPSC-ITGA6<sup>+</sup> 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<sup>+</sup> 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<sup>+</sup> 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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年10月27日

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  • 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,
  • Xinhui Xing,
  • Xinyu Ge,
  • Zhishang Chang,
  • Jinshan Tan,
  • Jingxue Zhang,
  • Bingqiang Zhang,
  • Qilong Cao,
  • Wenhua Xu,
  • Markus H. Kuehn,
  • Ningli Wang,
  • Wei Zhu

摘要

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.