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An efficient, non-viral arrayed CRISPR screening platform for iPSC-derived myeloid and microglia models
Sonja Meier1, Anne Sofie Gry Larsen2, Florian Wanke1
1Pharma Research and Early Development, Neuroscience and Rare Diseases, F. Hoffmann-La Roche Ltd, 4070 Basel, Switzerland.
Stem Cell Reports
|February 21, 2025
Summary
Researchers used CRISPR-Cas9 gene editing to study lipid handling in human microglia. They found the mTORC1 pathway is crucial for lipid storage, impacting Alzheimer's disease and neuroinflammation research.
Area of Science:
- Neuroscience
- Genetics
- Cell Biology
Background:
- Lipid metabolism is increasingly recognized as a key factor in neuroinflammation and Alzheimer's disease (AD).
- Microglia, the brain's immune cells, play a critical role in AD pathogenesis, and their lipid handling is a significant area of investigation.
- Understanding the genetic regulators of lipid metabolism in microglia is essential for developing novel therapeutic strategies for AD.
Purpose of the Study:
- To investigate lipid handling pathways in human induced pluripotent stem cell (iPSC)-derived microglia using a CRISPR-Cas9 arrayed screen.
- To identify key regulators of lipid droplet formation, particularly those dependent on Apolipoprotein E (APOE).
- To explore the role of the Mammalian Target of Rapamycin Complex 1 (mTORC1) signaling pathway in microglial lipid storage.
Main Methods:
- Development of a CRISPR-Cas9 arrayed screening platform for genetic perturbations in iPSC-derived myeloid cells.
- Establishment of a robust nucleofection method for delivering CRISPR-Cas9 ribonucleoprotein complexes.
- Performance of a targeted screen to identify regulators of APOE-dependent lipid droplet formation.
Main Results:
- Identification of the mTORC1 signaling pathway as a critical modulator of lipid storage in microglia.
- Demonstration of mTORC1's role in both APOE3 and APOE knockout microglial lipid handling.
- Validation of CRISPR-Cas9 technology for functional genomic studies in iPSC-derived microglia.
Conclusions:
- The mTORC1 pathway is a key regulator of lipid storage in human microglia, with implications for AD.
- CRISPR-Cas9 screening is a powerful tool for dissecting lipid metabolism pathways in disease-relevant cellular models.
- This study provides a foundation for further research into lipid dysregulation in neuroinflammation and Alzheimer's disease.
