Deciphering cellular interactions in CNS macrophage niches in mice and humans by spatial proteogenomics

Prof. Dr. Marco Prinz

• A01
• B07

Dr. Lukas Amann

• A01

Project Summary

Central nervous system (CNS)-associated macrophages (CAMs) are integral components of all CNS border regions, which include structures such as the meninges or the perivascular spaces (PVS) along the parenchymal blood vasculature. CAMs sett le the CNS interfaces in mouse and human in a stepwise fashion during embryonic and perinatal development, where they form disti nct subpopulations and adopt region-specific phenotypes over time. Local tissue- and contextspecific signals from neighbouring cells are thought to control functional features of CAMs. However, the identity of these cellular interactions of CAMs to tissue-specific adjacent cells, especially stromal cells is largely unknown. Furthermore, the distinct local anatomical niches that govern CAMs properties are underexplored. Here, in a cross-species approach, we will investigate CAMs in CNS interfaces and characterize their local environment by combining single-cell sequencing with spatial mapping of mRNA and proteins. We will first explore in mice and humans the anatomical niches of CAMs and their reciprocal and dynamic interplay with adjacent cells under homeostatic conditions using spatial proteogenomics (Aim 1). We will further thoroughly characterize the dynamics of CAMs interactions with defined stromal cells such as fibroblasts (Aim 2). Next, we will probe the molecular mechanisms by
which niche cells shape CAMs homeostasis (Aim 3). Finally, in a translational approach, we will examine CAMs features and cellular interactions during congenital cytomegalovirus infection in mouse and humans (Aim 4). The parallel analysis of human and murine tissue will allow to identify conserved interactions and pathways and to directly manipulate these pathways in transgenic mouse models. This project will provide insights into the endogenous immune system at CNS borders during ontogeny, homeostasis and perturbation.