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Updated: Sep 26, 2025
Generation of Human Microglia to Combine Them with Retinal Organoids for Improved Disease Modeling
Published on: July 26, 2024
Functional microglia derived from human pluripotent stem cells empower retinal organ
Mei-Ling Gao1, Xiao Zhang2, Fang Han2
1Institute of Stem Cell Research, The Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, China.
Abstract:
Microglia are known to play essential roles in the development, progression and treatment of diverse neurodegenerative diseases in the central nervous system, including the retina, brain and spinal cord. Recently, brain-induced microglia-like cells (iMGs) have been generated from human pluripotent stem cells (hPSCs); however, retinal microglia have yet to be developed in vitro. In this study, by mimicking in vivo microglial development, we established a simplified approach to differentiate hPSCs into high purity (>90%) iMGs. The iMGs express microglia-specific markers, release cytokines upon stimulation, and are capable of phagocytizing bacteria. When co-cultured with three-dimensional human retinal organoids (hROs), iMGs migrated into the hROs, tended to differentiate into resident retinal microglia, and simultaneously induced apoptosis in some neural cells. Notably, the resident iMGs in the hROs formed sparse web-like structures beneath the photoreceptor cell layer, resembling microglia's orientation in human retina. In conclusion, we developed a simplified and efficient method to generate microglia from human pluripotent stem cells, and we report the first derivation of retinaresident microglia in vitro, providing a new source of human retinal microglia for developmental and disease studies and regenerative therapeutics.
Insights
Researchers developed a simplified method to generate human retinal microglia from pluripotent stem cells. This breakthrough provides a new source for studying retinal diseases and developing regenerative therapies.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Ophthalmology
Background:
- Microglia are crucial in neurodegenerative diseases affecting the central nervous system, including the retina.
- Previous research generated brain-induced microglia-like cells (iMGs) from human pluripotent stem cells (hPSCs), but retinal microglia lacked in vitro models.
- Understanding retinal microglia is vital for neurodegenerative disease research and therapeutic development.
Purpose of the Study:
- To establish a simplified and efficient method for differentiating hPSCs into high-purity iMGs.
- To investigate the behavior and characteristics of these iMGs when co-cultured with human retinal organoids (hROs).
- To report the first successful derivation of retina-resident microglia in vitro.
Main Methods:
- Mimicking in vivo microglial development to differentiate hPSCs into iMGs with >90% purity.
- Characterizing iMGs by assessing microglia-specific markers, cytokine release upon stimulation, and phagocytic activity.
- Co-culturing iMGs with 3D hROs to observe migration, differentiation, and interaction with retinal cells.
Main Results:
- Generated high-purity iMGs (>90%) from hPSCs using a simplified differentiation protocol.
- Confirmed iMGs express microglia markers, release cytokines, and exhibit phagocytosis.
- Observed iMGs migrating into hROs, differentiating into resident retinal microglia, and inducing neural cell apoptosis.
- Demonstrated iMGs forming web-like structures in hROs, mimicking in vivo retinal microglia orientation.
Conclusions:
- Developed a simplified and efficient method for generating microglia from hPSCs.
- Successfully derived retina-resident microglia in vitro for the first time.
- Established a valuable new source of human retinal microglia for research and therapeutic applications.
