Human microglial cells as a therapeutic target in a neurodevelopmental disease model
Pinar Mesci1, Christopher N LaRock2, Jacob J Jeziorski1
1University of California, San Diego, School of Medicine, Department of Pediatrics/Rady Children's Hospital San Diego, Department of Cellular & Molecular Medicine, La Jolla, CA 92037, USA.
Abstract:
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.
Insights
Methyl-CpG binding protein 2 (MECP2) regulates human microglia function, impacting neurodevelopment. A CD11b agonist, ADH-503, restored microglial phagocytosis and offers a potential therapy for MECP2-related disorders.
Area of Science:
- Neuroscience
- Immunology
- Genetics
Background:
- Microglia, the immune cells of the central nervous system, have roles beyond immunity.
- Human microglial involvement in neurodevelopment is understudied due to tissue accessibility limitations.
Purpose of the Study:
- To investigate the impact of methyl-CpG binding protein 2 (MECP2) gene disruption on human microglia.
- To explore the role of microglia in human neurodevelopment and synapse formation.
- To identify potential therapeutic targets for MECP2-related conditions.
Main Methods:
- MECP2 gene knockout in human microglia-like cells (MGLs).
- Transcriptional profiling and functional assays (e.g., phagocytosis).
- Co-culture systems with neurons and MGLs.
- Drug screening and in vivo studies using MeCP2-null mice.
Main Results:
- MECP2 disruption in MGLs caused transcriptional and functional changes, including impaired phagocytosis.
- MGLs play a role in synaptogenesis, as evidenced by co-culture experiments.
- The CD11b agonist ADH-503 restored MGL phagocytosis and synapse formation, improving outcomes in a mouse model.
Conclusions:
- MECP2 specifically regulates human microglial phagocytosis.
- Microglia are crucial for synapse formation during neurodevelopment.
- ADH-503 represents a promising therapeutic strategy for MECP2-related disorders.
