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iPSC-derived microglia: Decoding roles and therapeutic opportunities in neurodegenerative diseases
Didi Shan1, Hongxu Wang1, Jianing Li1
1Department of Neurology, Research Institute of Neuromuscular and Neurodegenerative Diseases, Qilu Hospital of Shandong University, Shandong Key Laboratory of Mitochondrial Medicine and Rare Diseases, Jinan, Shandong 250012, China.
Abstract:
Microglia originate from erythro-myeloid progenitors (EMPs) in the early embryonic yolk sac and migrate into the developing brain, where they differentiate and mature under the regulation of chemokines, cytokines, and growth factors. As resident immune cells in the central nervous system (CNS), microglia maintain neural homeostasis by sensing the microenvironment, clearing pathogens, phagocytosing cellular debris, and modulating neuroinflammation and tissue repair. In response to injury or pathological stimuli, microglia adopt diverse activation states and contribute to synaptic remodeling, neuroimmune signaling, and neuroplasticity. Their pronounced functional heterogeneity during normal neurodevelopment and across diverse neurological disorders underscores the need for robust in vitro models. Human induced pluripotent stem cells (hiPSCs)-derived microglia have emerged as a powerful platform to investigate microglial development, neuroinflammatory responses, and microglia-mediated neurodegeneration. This review summarizes current hiPSCs-to-microglia differentiation strategies, highlighting their advantages, limitations, and applications. We further discuss the application of hiPSCs-derived microglia in modeling neurodegenerative diseases and critically evaluate the opportunities and challenges associated with beneficially modulating microglial function in the contexts of microglial depletion and replacement therapies.
Insights
Human induced pluripotent stem cells (hiPSCs) offer a powerful method to generate microglia for studying neurological disorders. These hiPSC-derived microglia are crucial for understanding neuroinflammation and developing new therapies.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Microglia, the resident immune cells of the central nervous system (CNS), originate from embryonic yolk sac progenitors.
- They play critical roles in neural development, homeostasis, and response to injury by clearing debris and modulating neuroinflammation.
- Functional heterogeneity of microglia in development and disease necessitates effective in vitro models.
Purpose of the Study:
- To review current strategies for differentiating human induced pluripotent stem cells (hiPSCs) into microglia.
- To highlight the applications, advantages, and limitations of hiPSC-derived microglia models.
- To discuss the potential of these models in studying neurodegenerative diseases and therapeutic strategies.
Main Methods:
- Review of existing literature on hiPSC-to-microglia differentiation protocols.
- Analysis of the utility of hiPSC-derived microglia in disease modeling.
- Evaluation of therapeutic approaches involving microglial modulation.
Main Results:
- hiPSCs provide a viable source for generating microglia-like cells.
- These cells serve as a valuable platform for investigating microglial functions in vitro.
- Differentiation strategies vary in efficiency and maturity of the derived microglia.
Conclusions:
- hiPSC-derived microglia are instrumental for advancing research in neuroinflammation and neurodegenerative diseases.
- These models offer opportunities for drug screening and personalized medicine.
- Further research is needed to optimize differentiation and fully leverage their therapeutic potential.
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