Project Summary

In ischemic stroke, adult neural stem/precursor cells (NSPCs) of the subventricular zone redirect their migration path to the lesion area and contribute to the remodeling of the injured brain. Along their trail to the lesion area, NSPCs encounter different CNS resident and infiltrating myeloid cell subsets, on which they may exert an immunomodulatory effect, and which may in turn affect their regenerative potential. In order to establish the functional significance of NSPC-myeloid cell crosstalk, we propose to use novel pharmacological or genetic tools (SDF-1 inhibition, CSF1R inhibition, conditional diphtheria toxin expression) to specifically ablate different NSPC or myeloid cell populations. The effect of either manipulation on the immune response and the migration and cellular fate of NSPCs will be assessed using flow-cytometry, immunohistochemistry as well as longitudinal two-photon imaging of isolated tissue or in vivo. Whole-transcriptome analysis of isolated NSPC and myeloid cell subtypes, focusing on receptor-ligand pairs, will enable us to identify molecules responsible for NSPC-myeloid cell interaction. Finally, we will examine the potential of a pharmaceutical modulation of the identified NSPC-myeloid cell receptor-ligand interactions on neuronal regeneration. This study will identify the contribution of the NSPC-myeloid cell communication on regeneration after stroke, potentially discovering mechanisms applicable to other inflammatory conditions of the CNS.