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Updated: Aug 25, 2025
Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
Published on: May 31, 2022
Deterministic programming of human pluripotent stem cells into microglia facilitates studying their role in health
Anna M Speicher1, Lisanne Korn1, Júlia Csatári1
1Department of Neurology with Institute of Translational Neurology, Universitätsklinikum Münster, 48149 Münster, Germany.
Abstract:
Microglia, the resident immune cells of the central nervous system (CNS), are derived from yolk-sac macrophages that populate the developing CNS during early embryonic development. Once established, the microglia population is self-maintained throughout life by local proliferation. As a scalable source of microglia-like cells (MGLs), we here present a forward programming protocol for their generation from human pluripotent stem cells (hPSCs). The transient overexpression of PU.1 and C/EBPβ in hPSCs led to a homogenous population of mature microglia within 16 d. MGLs met microglia characteristics on a morphological, transcriptional, and functional level. MGLs facilitated the investigation of a human tauopathy model in cortical neuron-microglia cocultures, revealing a secondary dystrophic microglia phenotype. Single-cell RNA sequencing of microglia integrated into hPSC-derived cortical brain organoids demonstrated a shift of microglia signatures toward a more-developmental in vivo-like phenotype, inducing intercellular interactions promoting neurogenesis and arborization. Taken together, our microglia forward programming platform represents a tool for both reductionist studies in monocultures and complex coculture systems, including 3D brain organoids for the study of cellular interactions in healthy or diseased environments.
Insights
Researchers developed a new method to create human microglia-like cells from pluripotent stem cells. These cells mimic natural microglia and aid in studying neurological diseases like tauopathy.
Area of Science:
- Neuroscience
- Immunology
- Stem Cell Biology
Background:
- Microglia are the central nervous system's immune cells, originating from yolk-sac macrophages.
- The microglia population is self-sustaining throughout life via local proliferation.
Purpose of the Study:
- To establish a scalable method for generating microglia-like cells (MGLs) from human pluripotent stem cells (hPSCs).
- To characterize the generated MGLs and assess their utility in disease modeling.
Main Methods:
- Forward programming of hPSCs via transient overexpression of PU.1 and C/EBPβ.
- Morphological, transcriptional, and functional characterization of generated MGLs.
- Co-culture of MGLs with human tauopathy models and integration into hPSC-derived brain organoids.
Main Results:
- A homogenous population of mature MGLs was generated within 16 days.
- MGLs exhibited microglia-specific characteristics and revealed a dystrophic microglia phenotype in a tauopathy model.
- Microglia integrated into brain organoids displayed an in vivo-like developmental phenotype, promoting neurogenesis and arborization.
Conclusions:
- The developed forward programming platform provides a scalable source of MGLs.
- This platform enables reductionist and complex 3D model systems for studying microglia in health and disease.
- MGLs are valuable tools for investigating cellular interactions in neurological disorders.
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