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Updated: May 23, 2025
Transplantation of Human Induced Pluripotent Stem Cell-Derived Microglia in Immunocompetent Mice Brain via Non-Invasive Transnasal Route
Published on: May 31, 2022
A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases
Lutgarde Serneels1, Annerieke Sierksma1, Emanuela Pasciuto2
1VIB Center for Brain and Disease Research and Department of Neurosciences, KU Leuven, Louvain, Belgium.
Background:
Recent studies highlight the critical role of microglia in neurodegenerative disorders, and emphasize the need for humanized models to accurately study microglial responses. Human-mouse microglia xenotransplantation models are a valuable platform for functional studies and for testing therapeutic approaches, yet currently those models are only available for academic research. This hampers their implementation for the development and testing of medication that targets human microglia.
Methods:
We developed the hCSF1Bdes mouse line, which is suitable as a new transplantation model and available to be crossed to any disease model of interest. The hCSF1Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additionally, we crossed this model with two humanized App KI mice, the AppHu and the AppSAA. Flow cytometry, immunohistochemistry and bulk sequencing was used to study the response of microglia in the context of Alzheimer's disease.
Results:
Our results demonstrate the successful transplantation of iPSC-derived human microglia into the brains of hCSF1Bdes mice without triggering a NK-driven immune response. Furthermore, we confirmed the multipronged response of microglia in the context of Alzheimer's disease. The hCSF1Bdes and the crosses with the Alzheimer's disease knock-in model AppSAA and the humanized App knock-in control mice, AppHu are deposited with EMMA and fully accessible to the research community.
Conclusion:
The hCSF1Bdes mouse is available for both non-profit and for-profit organisations, facilitating the use of the xenotransplantation paradigm for human microglia to study complex human disease.
Insights
Researchers developed a new humanized mouse model for studying microglia in neurodegenerative diseases. This model enables the testing of new medications targeting human microglia, accelerating therapeutic development.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia play a critical role in neurodegenerative disorders.
- Humanized mouse models are essential for studying microglial responses.
- Current models are limited to academic research, hindering drug development.
Purpose of the Study:
- To develop a novel humanized mouse model for microglia xenotransplantation.
- To facilitate the study and therapeutic targeting of human microglia in disease contexts.
- To make this model accessible to both academic and industry researchers.
Main Methods:
- Development of the hCSF1Bdes mouse line using CRISPR gene editing.
- Crossing hCSF1Bdes mice with humanized App KI models (AppHu and AppSAA).
- Utilizing flow cytometry, immunohistochemistry, and bulk sequencing for analysis.
Main Results:
- Successful transplantation of iPSC-derived human microglia into hCSF1Bdes mice without immune rejection.
- Demonstrated the complex response of human microglia in an Alzheimer's disease context.
- Deposited the developed mouse lines (hCSF1Bdes, AppSAA, AppHu) with EMMA for community access.
Conclusions:
- The hCSF1Bdes mouse model enables xenotransplantation of human microglia.
- This model supports the study of human microglia in complex diseases like Alzheimer's.
- Availability to non-profit and for-profit organizations accelerates therapeutic research.
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