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

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

doi:10.1038/s41467-025-65475-8

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

Journal article

Open access

Peer reviewed

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

Pengchao Feng, Chen Yu, Xiaoyan Zhang, Bin Xu, Shen Wu, Chen Xin, Sejiro Littleton, Jie Kang, Xiangji Wang, Shaoshuai Liang, …

Nature communications, Vol.16(1), 9441

10/27/2025

DOI: 10.1038/s41467-025-65475-8

PMCID: PMC12559184

PMID: 41145463

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https://doi.org/10.1038/s41467-025-65475-8View

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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.

Animals

Aqueous Humor - metabolism

Cell Proliferation

Cells, Cultured

Female

Glaucoma - metabolism

Glaucoma - pathology

Glaucoma - therapy

Glaucoma, Open-Angle - metabolism

Glaucoma, Open-Angle - pathology

Glaucoma, Open-Angle - therapy

Humans

Induced Pluripotent Stem Cells - cytology

Induced Pluripotent Stem Cells - metabolism

Integrin alpha6 - genetics

Integrin alpha6 - metabolism

Male

Mice

RNA, Long Noncoding - genetics

RNA, Long Noncoding - metabolism

Trabecular Meshwork - cytology

Trabecular Meshwork - metabolism

Details

Title: Subtitle: iPSC-derived ITGA6-positive cells restore aqueous humor outflow in glaucoma eyes
Creators: Pengchao Feng - Qingdao University
Chen Yu - Duke University School of Medicine
Xiaoyan Zhang - Qingdao University
Bin Xu - Ocean University of China
Shen Wu - Beijing Tongren Hospital
Chen Xin - Beijing Tongren Hospital
Sejiro Littleton - Duke University
Jie Kang - Ocean University of China
Xiangji Wang - Qingdao University
Shaoshuai Liang - Qingdao Restore Biotechnology Co., Ltd., Qingdao, China
Susu Chen - Qingdao University
Wenyan Wang - Qingdao University
Yanan Wang - Qingdao University
Zhixin Yuan - Haier
Gaiping Xi - Qingdao University
Xinhui Xing - Qingdao University
Xinyu Ge - Qingdao University
Zhishang Chang - Qingdao University
Jinshan Tan - Qingdao University
Jingxue Zhang - Beijing Tongren Hospital
Bingqiang Zhang - Qingdao Restore Biotechnology Co., Ltd., Qingdao, China
Qilong Cao - Haier Group
Wenhua Xu - Qingdao University
Markus H Kuehn - University of Iowa
Ningli Wang - Capital Medical University
Wei Zhu - Qingdao University
Resource Type: Journal article
Publication Details: Nature communications, Vol.16(1), 9441
DOI: 10.1038/s41467-025-65475-8
PMID: 41145463
PMCID: PMC12559184
NLM abbreviation: Nat Commun
ISSN: 2041-1723
eISSN: 2041-1723
Publisher: NATURE PORTFOLIO
Grant note: tsqn202103055 / Taishan Scholar Foundation of Shandong Province L212036 / Natural Science Foundation of Beijing Municipality (Beijing Natural Science Foundation)
Language: English
Date published: 10/27/2025
Academic Unit: Ophthalmology and Visual Sciences
Record Identifier: 9985019037002771

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