A novel in vivo human-mouse chimeric brain model to study human microglia specification and contributions to neuropsychiatric disease

To understand and study human microglia function in health and disease, there is an unmet need for human cell-based models that feature functionally mature cells operating within a physiologically-relevant environment.

This project will set out to characterize a novel humanized model system to advance the study of human-specific microglia states and functions in health and disease.
To achieve this, we have developed an approach that mimics the colonization of human brain organoids through human erythromyeloid progenitors and capitalizes on our ability to graft these units into a rodent host for vascularization. Taking advantage of this approach, we shall first comprehensively profile and compare microglia states in our humanized neuro-immune models to human brain tissue using single cell transcriptomics, immunohistochemistry and mass cytometry. We will then aim to generate gender-specific neuro-immune models to assess environment-specific and intrinsic factors that contribute to sexual dimorphism of microglia in humans.
By combining intravital microscopy, high-throughput molecular profiling and advanced immunohistochemistry, we aim to focus in particular on those microglia states and functions that shape early prenatal stages of human brain development. We shall further use this model to assess if sex differences in endogenous microglia functions or the brain environment may in part be responsible for sexual dimorphic responses under specific pathological conditions.

In summary, the suggested experiments will allow us to study the context-specific complexity of human microglia states and function and enable us to reveal the cellular and molecular mechanisms that contribute to their sexual dimorphic behavior in healthy and diseased brains. An in-depth assessment of both, human microglia and the surrounding cells that make up the human brain environment, will give us the unprecedented opportunity to investigate human-specific aspects of the dynamic interactions of microglia with neurons, macroglia and neurovascular cells.