一种用于推进神经退行性疾病中人类小胶质细胞移植研究的通用小鼠模型。

A versatile mouse model to advance human microglia transplantation research in neurodegenerative diseases.

作者信息

Serneels Lutgarde, Sierksma Annerieke, Pasciuto Emanuela, Geric Ivana, Nair Arya, Martinez-Muriana Anna, Snellinx An, De Strooper Bart

机构信息

VIB Center for Brain and Disease Research and Department of Neurosciences, KU Leuven, Louvain, Belgium.

VIB Center for Molecular Neurology and Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

出版信息

Mol Neurodegener. 2025 Mar 11;20(1):29. doi: 10.1186/s13024-025-00823-2.

DOI:10.1186/s13024-025-00823-2

PMID:40069774

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11895352/

Abstract

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 mouse line, which is suitable as a new transplantation model and available to be crossed to any disease model of interest. The hCSF1 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 App and the App. 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 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 and the crosses with the Alzheimer's disease knock-in model App and the humanized App knock-in control mice, App are deposited with EMMA and fully accessible to the research community.

CONCLUSION

The hCSF1 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.

摘要

背景

最近的研究突出了小胶质细胞在神经退行性疾病中的关键作用，并强调需要人性化模型来准确研究小胶质细胞反应。人鼠小胶质细胞异种移植模型是功能研究和测试治疗方法的宝贵平台，但目前这些模型仅用于学术研究。这阻碍了它们在针对人类小胶质细胞的药物开发和测试中的应用。

方法

我们开发了hCSF1小鼠品系，它适合作为一种新的移植模型，可与任何感兴趣的疾病模型进行杂交。通过CRISPR基因编辑创建的hCSF1模型缺乏RAG2并表达人类CSF1。此外，我们将该模型与两种人源化的App KI小鼠（App和App）进行杂交。使用流式细胞术、免疫组织化学和大量测序来研究阿尔茨海默病背景下小胶质细胞的反应。

结果

我们的结果表明，诱导多能干细胞衍生的人类小胶质细胞成功移植到hCSF1小鼠大脑中，且未引发自然杀伤细胞驱动的免疫反应。此外，我们证实了阿尔茨海默病背景下小胶质细胞的多方面反应。hCSF1以及与阿尔茨海默病基因敲入模型App和人源化App基因敲入对照小鼠App的杂交品系已存入EMMA，可供研究界全面使用。