Decoding human microglia phenotypes in the context of neuropsychiatric disorders

Prof. Dr. Simon Schäfer

• A11N

Prof. Dr. Josef Priller

• A11N
• B07
• IRTG

Project Summary

While core microglial programmes are preserved across different species, many patterns of gene expression differ and some of these appear to pertain specifically to factors that are implicated in human-specific disorders. This project will harness human induced pluripotent stem cell (iPSC) technologies and three-dimensional (3D) tissue engineering approaches in order to decode context-specific human microglia states in healthy and diseased human brain environments.
Our goal is to uncover the pathways involved in driving the acquisition of context-specific human microglia states as well as those that lead to their functional derailment in neuropsychiatric disorders. To achieve this goal, we will leverage a versatile set of organoid technologies, which we have previously developed, in order to generate models that can capture context-dependent brain-microglia interactions. Here, we will first set out to characterize the molecular mechanisms that are driving context-dependent diversification of human microglia states and phenotypes in a model of the developing human forebrain (Aim 1). Using CRISPR-based perturbation assays (CRISPRa/i), we will identify molecular and cellular mediators that orchestrate the acquisition of context-dependent human microglia states in our model (Aim 2). Finally, we shall generate human patient-derived disease models using clinically well-stratified cohorts of patients with Autism
Spectrum Disorder (ASD) and Huntington’s disease (HD) that show specific aberrations in the development of the cortex, resulting in complex neurological and psychiatric symptoms and a disease-associated shift in microglia phenotypes. Using these patient-specific disease models will allow us to i) elucidate how disease-associated microglia phenotypes emerge in ASD and HD and ii) to assess the consequences these cellular phenotypes pose for the development and function of the human brain (Aim 3). To realize these aims, we plan to pursue a multidisciplinary approach that brings together human stem cell-based technologies, dynamic imaging approaches, functional cell biology and single cell genomics.