Patient-specific models of microglia-mediated engulfment of synapses and neural progenitors
C M Sellgren1,2,3, S D Sheridan1,2, J Gracias1,2
1Center for Experimental Drugs and Diagnostics, Center for Human Genetic Research and Department of Psychiatry, Massachusetts General Hospital, Boston, MA, USA.
Abstract:
Engulfment of synapses and neural progenitor cells (NPCs) by microglia is critical for the development and maintenance of proper brain circuitry, and has been implicated in neurodevelopmental as well as neurodegenerative disease etiology. We have developed and validated models of these mechanisms by reprogramming microglia-like cells from peripheral blood mononuclear cells, and combining them with NPCs and neurons derived from induced pluripotent stem cells to create patient-specific cellular models of complement-dependent synaptic pruning and elimination of NPCs. The resulting microglia-like cells express appropriate markers and function as primary human microglia, while patient-matched macrophages differ markedly. As a demonstration of disease-relevant application, we studied the role of C4, recently implicated in schizophrenia, in engulfment of synaptic structures by human microglia. The ability to create complete patient-specific cellular models of critical microglial functions utilizing samples taken during a single clinical visit will extend the ability to model central nervous system disease while facilitating high-throughput screening.
Insights
Researchers created patient-specific models of microglia function to study brain development and disease. These models help investigate synaptic pruning and neural progenitor cell elimination, crucial for understanding neurological disorders.
Area of Science:
- Neuroscience
- Cell Biology
- Immunology
Background:
- Microglial engulfment of synapses and neural progenitor cells (NPCs) is vital for brain development and circuitry.
- Dysfunctional microglial activity is linked to neurodevelopmental and neurodegenerative diseases.
Purpose of the Study:
- To develop patient-specific cellular models of microglial functions, including synaptic pruning and NPC elimination.
- To investigate the role of complement C4 in microglial engulfment, particularly in the context of schizophrenia.
Main Methods:
- Reprogramming peripheral blood mononuclear cells into microglia-like cells.
- Utilizing induced pluripotent stem cells to derive NPCs and neurons.
- Creating patient-specific cellular co-culture models.
Main Results:
- Generated microglia-like cells that express appropriate markers and function like primary human microglia.
- Demonstrated patient-specific modeling of complement-dependent synaptic pruning and NPC elimination.
- Showcased disease-relevant application by studying C4's role in microglial engulfment.
Conclusions:
- Developed a robust platform for patient-specific modeling of critical microglial functions.
- This approach facilitates the study of central nervous system diseases and enables high-throughput screening.
- The models offer a powerful tool for understanding microglial roles in health and disease.
