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Updated: Jun 8, 2025
Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
Published on: May 31, 2022
Human-induced pluripotent stem cell-derived microglia integrate into mouse retina and recapitulate features of
Wenxin Ma1, Lian Zhao2, Biying Xu3
1Retinal Neurophysiology Section, National Eye Institute, Bethesda, United States.
Abstract:
Microglia exhibit both maladaptive and adaptive roles in the pathogenesis of neurodegenerative diseases and have emerged as a cellular target for central nervous system (CNS) disorders, including those affecting the retina. Replacing maladaptive microglia, such as those impacted by aging or over-activation, with exogenous microglia that can enable adaptive functions has been proposed as a potential therapeutic strategy for neurodegenerative diseases. To investigate microglia replacement as an approach for retinal diseases, we first employed a protocol to efficiently generate human-induced pluripotent stem cell (hiPSC)-derived microglia in quantities sufficient for in vivo transplantation. These cells demonstrated expression of microglia-enriched genes and showed typical microglial functions such as LPS-induced responses and phagocytosis. We then performed xenotransplantation of these hiPSC-derived microglia into the subretinal space of adult mice whose endogenous retinal microglia have been pharmacologically depleted. Long-term analysis post-transplantation demonstrated that transplanted hiPSC-derived microglia successfully integrated into the neuroretina as ramified cells, occupying positions previously filled by the endogenous microglia and expressed microglia homeostatic markers such as P2ry12 and Tmem119. Furthermore, these cells were found juxtaposed alongside residual endogenous murine microglia for up to 8 months in the retina, indicating their ability to establish a stable homeostatic state in vivo. Following retinal pigment epithelial cell injury, transplanted microglia demonstrated responses typical of endogenous microglia, including migration, proliferation, and phagocytosis. Our findings indicate the feasibility of microglial transplantation and integration in the retina and suggest that modulating microglia through replacement may be a therapeutic strategy for treating neurodegenerative retinal diseases.
Insights
Replacing dysfunctional microglia with lab-grown cells offers a promising therapy for neurodegenerative retinal diseases. Human stem cell-derived microglia successfully integrated into mouse retinas, restoring normal function and suggesting a new treatment avenue.
Area of Science:
- Neuroscience
- Stem Cell Biology
- Ophthalmology
Background:
- Microglia play dual roles in neurodegenerative diseases, impacting the central nervous system (CNS), including the retina.
- Replacing maladaptive microglia with functional, exogenous microglia is a proposed therapeutic strategy for CNS disorders.
- Investigating microglia replacement for retinal diseases requires efficient generation and transplantation of functional microglia.
Purpose of the Study:
- To assess the feasibility of using human-induced pluripotent stem cell (hiPSC)-derived microglia for transplantation in the retina.
- To evaluate the integration, survival, and functional capacity of transplanted microglia in a mouse model.
- To determine if microglial replacement can serve as a therapeutic approach for neurodegenerative retinal diseases.
Main Methods:
- Generated human-induced pluripotent stem cell (hiPSC)-derived microglia exhibiting characteristic gene expression and functions.
- Performed xenotransplantation of hiPSC-derived microglia into the subretinal space of pharmacologically treated mice with depleted endogenous microglia.
- Analyzed long-term integration, survival, homeostatic marker expression, and functional responses of transplanted microglia in vivo.
Main Results:
- hiPSC-derived microglia were generated in sufficient quantities for transplantation and demonstrated microglial functions.
- Transplanted microglia successfully integrated into the mouse neuroretina, adopting ramified morphology and expressing homeostatic markers.
- Integrated microglia persisted for up to 8 months, co-existed with residual endogenous microglia, and responded to injury by migrating, proliferating, and phagocytosing.
Conclusions:
- Microglial transplantation and integration into the retina are feasible using hiPSC-derived cells.
- Modulating microglia through cell replacement represents a potential therapeutic strategy for neurodegenerative retinal diseases.
- This study provides a foundation for developing cell-based therapies targeting retinal microglia in disease contexts.
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