iPSC-derived ITGA6-positive cells restore aqueous humor outflow in glaucoma eyes
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 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.
Authors
- Jingxue Zhang (ORCID: https://orcid.org/0000-0002-9512-9602)
- Markus H. Kuehn (ORCID: https://orcid.org/0000-0003-3940-198X)
- Jie Kang (ORCID: https://orcid.org/0000-0002-8991-2844)
- Pengchao Feng (ORCID: https://orcid.org/0009-0005-6321-4983)
- Sejiro Littleton (ORCID: https://orcid.org/0000-0002-4845-4170)
- Bingqiang Zhang (ORCID: https://orcid.org/0000-0002-9149-3677)
- Yanan Wang (ORCID: https://orcid.org/0000-0002-7488-5070)
- Wei Zhu (ORCID: https://orcid.org/0000-0001-7003-2524)
- X H Wang (ORCID: https://orcid.org/0009-0004-9360-6956)
- Qilong Cao (ORCID: https://orcid.org/0000-0001-6280-4053)
- Susu Chen (ORCID: https://orcid.org/0009-0007-5906-2002)
- Zhi‐Xin Yuan (ORCID: https://orcid.org/0000-0003-4832-0997)
- Zengyi Chang (ORCID: https://orcid.org/0000-0002-8386-7499)
- Xiaoyan Zhang (ORCID: https://orcid.org/0009-0002-8339-2136)
- Ningli Wang (ORCID: https://orcid.org/0000-0002-8933-4482)
- Wenhua Xu (ORCID: https://orcid.org/0000-0001-7426-6950)
- Yu Chen (ORCID: https://orcid.org/0000-0001-9651-9875)
- Wenyan Wang (ORCID: https://orcid.org/0000-0002-3920-1390)
- Xinyu Ge
- Bin Xu (ORCID: https://orcid.org/0000-0003-0878-1094)
- Xin‐Hui Xing (ORCID: https://orcid.org/0000-0001-6419-4770)
- Jinshan Tan
- Gaiping Xi
- Shen Wu (ORCID: https://orcid.org/0000-0002-5669-0069)
- Chen Xin (ORCID: https://orcid.org/0000-0003-0851-8624)
- Shaoshuai Liang
Institutions
- Qingdao University (CN)
- University of Iowa (US)
- Beijing Tongren Hospital (CN)
- Qingdao Agricultural University (CN)
- Duke University (US)
- Capital Medical University (CN)
- Veterans Health Administration (US)
- Henan Academy of Sciences (CN)
- Chinese Institute for Brain Research (CN)
- Shandong Entry-Exit Inspection and Quarantine Bureau (CN)
- Haier Group (China) (CN)
- Qingdao Center of Resource Chemistry and New Materials (CN)
- Ocean University of China (CN)
- Tsinghua University (CN)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-10-27
- DOI
- https://doi.org/10.1038/s41467-025-65475-8
- Citations
- 2
- Primary Topic
- Glaucoma and retinal disorders
- Type
- article
- Field-Weighted Citation Impact
- 3.41
Funders
- Natural Science Foundation of Shandong Province
- Qingdao University
- National Key Research and Development Program of China