A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases
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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 hCSF1 Bdes mouse line suitable as new transplantation model available to be crossed to any disease model of interest. The hCSF1 Bdes model created by CRISPR gene editing is RAG2 deficient and expresses human CSF1. Additional we crossed this model with two humanized App KI mice, the App Hu and the App SAA . 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 hCSF1 Bdes mice without triggering a NK-driven immune response. Furthermore we confirmed the multipronged response of microglia in the context of Alzheimer’s disease. The hCSF1 Bdes and the crosses with the Alzheimer’s disease knock-in model App SAA and the humanized App knock-in control mice, App Hu are deposited with EMMA and fully accessible to the research community.
Conclusion
the hCSF1 Bdes 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.
