The role of pericyte signaling in the immune response after ischemic stroke

• Applicant: Dr. Steffen Haupeltshofer
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2024
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 549421914

Pericytes are uniquely positioned at the blood/brain interface guarding the homeostasis and microenvironment of the central nervous system. In response to hypoxia, pericytes are among the first responders representing a highly active signaling regulator at the blood brain barrier which has been suggested to control the pathological cascade during ischemic stroke. Among these mechanisms, pericytes were shown to inhabit features strongly correlating to macrophage function. The phenotype of macrophages in turn critically depends on their environment but was also shown to rely on the site of recruitment i.e. meninges which determines the inflammatory or neuroprotective phenotype. However, conclusive understanding of the interaction between pericytes and immune cells during cerebral ischemia remains elusive. We hypothesize that the dynamic nature of pericytes represents an unexplored modulatory hub that can be targeted to remotely influence the neuroinflammatory response in ischemic stroke. Therefore, our first goal is to identify significant pericyte-dependent changes in the immunological landscape at different time points after ischemic stroke in mouse models and in human stroke. In mouse models, we take advantage of a pericyte-specific knock-out model and deeply characterize immune cells using single-cell RNA sequencing; in humans we phenotype immune cells from post-mortem tissue via single-nucleus RNA sequencing. As a result, a comparative immune cell library identifying the impact of pericytes and including temporal changes during stroke progression will be established. Further, we define the spatial distribution of distinct immune cell phenotypes, in particular macrophages, within the infarct. We will validate the ability of pericytes to recruit macrophages to the ischemic brain from the periphery and meninges using conditional CCL-2 knock-out mice and meningeal immune cell labelling. Here we generate hypotheses of cellular crosstalk incorporating previous transcriptomic immune cells data and results from spatial immune cell imaging performed on mouse model brain sections and human stroke postmortem tissue. In the third step, we modulate pericytes and elucidate their impact on shifts in macrophage polarization in vitro and in vivo using conditional IL-11 knock-out mice. Taken together, we will assess the pathophysiological relevance of pericytes as a remote modulator for immune cell determination and verify pericytes as key targets in stroke pathophysiology. To achieve these goals, Lund University provides the perfect scientific environment at an international level.

• DFG Programme: WBP Fellowship
• International Connection: Sweden
• Host: Professorin Gesine Paul-Visse