Summary of the research programme
Myeloid cells in the central nervous system (CNS) represent a heterogeneous class of innate immune cells that differentially contribute to the maintenance of tissue homeostasis during development, adulthood and disease. Recent studies using cell-specific targeting, in vivo imaging, single-cell expression analysis and other sophisticated tools fundamentally changed our views on the origin, fate and function of distinct myeloid subsets in the CNS.
In the first funding period, we have made substantial research efforts to elucidate the role of microglia and other myeloid cells during health and brain diseases with a special focus on myeloid cell heterogeneity. Members of the CRC/TRR167 NeuroMac consortium introduced novel single-cell technologies into the field of neuroimmunology, such as single-cell RNA-sequencing (scRNA-Seq), single-cell sequencing assay for transposase-accessible chromatin-sequencing (scATAC-seq), single-cell mass cytometry (CyTOF), which allowed us to characterize for the first time different states of human microglia and discover targetable disease-associated microglia states.
In the second funding period, which was complicated by the restrictions imposed by the pandemic, we expanded the focus from microglia to CNS-associated macrophages (CAMs) in the meninges, choroid plexus and perivascular sites. We developed novel transgenic mouse models for differential gene targeting of both microglia and CAMs. We also profiled microglia and CAMs across a variety of CNS diseases. Most notably, we made important discoveries on the interactions of CNS myeloid cells with neighbouring cells, such as arterial smooth muscle cells, oligodendrocytes and neurons.
For the third funding period, we aim to increase our understanding of the cell-cell interactions and niche signals that instruct the development and function of microglia and CAMs in health and disease. We will introduce novel spatial genomic and proteomic tools, and consider sex and environmental influences. As the prospect of modulating myeloid cells for therapeutic purposes in CNS disorders has gained momentum in the consortium, we will use in vivo CRISPR-Cas9 perturbations to identify potential targets. We will focus on translating previous results of the consortium into the human context by employing humanized animal models, organoids, multi-dimensional single-cell technologies and biosamples from clinical cohorts. The inclusion of the Munich site with expertise on cutting-edge human stem cell-based technologies and high-resolution in vivo imaging will be instrumental in driving the research on human microglia and CAMs.
The long-term goal of the NeuroMac consortium is to facilitate the transfer of knowledge obtained from basic research on CNS myeloid cells to the improvement of patient care by providing sufficient preclinical evidence for translation, and by deciphering the fundamental mechanisms of myeloid cell biology in the CNS during health and disease.
