2024-07-25 カリフォルニア大学サンディエゴ校(UCSD)
<関連情報>
- https://today.ucsd.edu/story/cancer-drug-could-ease-cognitive-function-for-some-with-autism
- https://www.cell.com/stem-cell-reports/fulltext/S2213-6711(24)00193-0
神経発達疾患モデルにおける治療標的としてのヒトミクログリア細胞 Human microglial cells as a therapeutic target in a neurodevelopmental disease model
Pinar Mesci,Christopher N. LaRock,Jacob J. Jeziorski,…,Kinichi Nakashima,Victor Nizet,Alysson R. Muotri,,
Stem Cell Reports Published:July 25, 2024
DOI:https://doi.org/10.1016/j.stemcr.2024.06.013
Highlights
- MECP2 is implicated in microglial functions including phagocytosis
- Human microglia are implicated in synapse formation
- CD11b agonist ADH-503 restored phagocytosis and synaptic defects and increased survival
- Human microglia can be promising therapeutic targets for neurological conditions
Summary
Although microglia are macrophages of the central nervous system, their involvement is not limited to immune functions. The roles of microglia during development in humans remain poorly understood due to limited access to fetal tissue. To understand how microglia can impact human neurodevelopment, the methyl-CpG binding protein 2 (MECP2) gene was knocked out in human microglia-like cells (MGLs). Disruption of the MECP2 in MGLs led to transcriptional and functional perturbations, including impaired phagocytosis. The co-culture of healthy MGLs with MECP2-knockout (KO) neurons rescued synaptogenesis defects, suggesting a microglial role in synapse formation. A targeted drug screening identified ADH-503, a CD11b agonist, restored phagocytosis and synapse formation in spheroid-MGL co-cultures, significantly improved disease progression, and increased survival in MeCP2-null mice. These results unveil a MECP2-specific regulation of human microglial phagocytosis and identify a novel therapeutic treatment for MECP2-related conditions.
Graphical abstract
