Xie QQ, Zeng MQ, Mao LN, Han SJ, Sun D, Zheng ZG. Multilayered control of retinal stem/progenitor cell fate in the single-cell and organoid era: Developmental blueprints and regenerative opportunities. World J Stem Cells 2026; 18(4): 118621 [DOI: 10.4252/wjsc.v18.i4.118621]
Corresponding Author of This Article
Zhi-Gang Zheng, MD, Chief, Professor, Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, No. 100 Minjiang Avenue, Quzhou 324000, Zhejiang Province, China. zhengzhigang0710@wmu.edu.cn
Research Domain of This Article
Cell & Tissue Engineering
Article-Type of This Article
Review
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Apr 26, 2026 (publication date) through Apr 22, 2026
Times Cited of This Article
Times Cited (0)
Journal Information of This Article
Publication Name
World Journal of Stem Cells
ISSN
1948-0210
Publisher of This Article
Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA
Share the Article
Xie QQ, Zeng MQ, Mao LN, Han SJ, Sun D, Zheng ZG. Multilayered control of retinal stem/progenitor cell fate in the single-cell and organoid era: Developmental blueprints and regenerative opportunities. World J Stem Cells 2026; 18(4): 118621 [DOI: 10.4252/wjsc.v18.i4.118621]
Qi-Qi Xie, Shi-Jun Han, School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, Zhejiang Province, China
Mei-Qi Zeng, Li-Ni Mao, Zhi-Gang Zheng, Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, Quzhou 324000, Zhejiang Province, China
Da Sun, Institute of Life Sciences and Biomedical Collaborative Innovation Center of Zhejiang Province, Wenzhou University, Wenzhou 325000, Zhejiang Province, China
Co-first authors: Qi-Qi Xie and Mei-Qi Zeng.
Author contributions: Xie QQ and Zeng MQ contributed equally to this work as co-first authors. Xie QQ and Zeng MQ contributed to conceptualization; Xie QQ contributed to literature review, data interpretation, and writing - original draft preparation; Zeng MQ contributed to funding acquisition, methodology design, data curation, and writing - review and editing; Mao LN contributed to investigation, figure/table preparation, and manuscript revision; Han SJ contributed to formal analysis, data visualization, and validation; Sun D contributed to literature screening, resources, and reference management; Zheng ZG conceived and supervised the study, provided critical review and editing, and approved the final version of the manuscript. All authors read and approved the final manuscript.
Supported by Quzhou Municipal Science and Technology Plan Project, No. ZD2022218 and No. ZD2022231.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Corresponding author: Zhi-Gang Zheng, MD, Chief, Professor, Department of Ophthalmology, The Quzhou Affiliated Hospital of Wenzhou Medical University, Quzhou People’s Hospital, No. 100 Minjiang Avenue, Quzhou 324000, Zhejiang Province, China. zhengzhigang0710@wmu.edu.cn
Received: January 7, 2026 Revised: February 22, 2026 Accepted: March 20, 2026 Published online: April 26, 2026 Processing time: 103 Days and 18 Hours
Abstract
Irreversible degeneration of retinal neurons and the retinal pigment epithelium is a major cause of vision loss, and current pharmacological or surgical treatments seldom rebuild lost tissue, placing stem cell-based regeneration at the center of therapeutic exploration. Retinal progenitor cells, Müller glia (MG)-derived progenitors, pluripotent stem cell-derived retinal pigment epithelium and photoreceptors, and emerging human retinal stem cell candidates together provide a diverse cellular repertoire whose behavior is governed by tightly coordinated fate-control mechanisms. Enabled by single-cell and spatial multi-omics in developing human retina and retinal organoids, these mechanisms can now be mapped at unprecedented resolution, revealing how distinct lineage trajectories and molecular states arise. This review synthesizes a multilayered framework of fate regulation encompassing the diversity and plasticity of embryonic progenitors, MG-derived progenitors, ciliary margin-like cells and putative adult retinal stem cells, and examines how transcription factor hierarchies, epigenetic landscapes, and non-coding RNAs interact with translational, metabolic and inflammatory cues to shape competence windows and photoreceptor vs inner retinal fates in development and disease. These insights are then connected to next-generation regenerative strategies, including engineered retinal organoids and sheets, MG reprogramming, and rational combinations of gene and cell therapies designed to precisely steer cell identity, maturation and circuit integration. By framing retinal regeneration within this multilayered control paradigm, we highlight key challenges for clinical translation and outline how targeted manipulation of fate-regulatory networks may accelerate the development of safe and effective stem cell therapies for blinding retinal disorders.
Core Tip: Retinal degeneration is a structural failure that cannot be reversed by pathway modulation alone. Leveraging single-cell and spatial multi-omics from human retina and organoids, this review defines a multilayer fate-control paradigm - transcriptional instruction, epigenetic permission, and metabolic/inflammatory execution - that governs competence windows and photoreceptor vs inner-retinal outcomes. We compare major regenerative cell sources (retinal progenitors, Müller glia, ciliary marginal zone-like candidates, and human pluripotent stem cell-derived retinal pigment epithelium/ photoreceptors) and translate atlas insights into actionable engineering strategies, including organoid benchmarking, staged reprogramming, and rational gene + cell combinations to enhance maturation and circuit integration.
