Single cell approaches define forebrain neural stem cell niches and identify microglial ligands that enhance precursor-mediated remyelination (MERFISH)

Here we used single cell RNA-sequencing and single cell spatial transcriptomics to characterize the forebrain neural stem cell (NSC) niche under homeostatic and injury conditions. We define the dorsal and lateral ventricular-subventricular zones (V-SVZ) as two distinct neighborhoods, and show that following white matter injury, dorsal NSCs are locally activated to make oligodendrocytes for remyelination. This activation is coincident with a robust increase in transcriptionally-distinct microglia in the dorsal V-SVZ niche. We modeled ligand-receptor interactions within this changing niche and identified two remyelination-associated microglial ligands, IGF1 and OSM, that promote precursor proliferation and oligodendrogenesis in culture. Infusion of either ligand into the lateral ventricles also enhanced oligodendrogenesis, even in the lateral V-SVZ, where NSCs normally make neuroblasts. These data support a model where gliogenesis versus neurogenesis is determined by the local NSC neighborhood and where injury-induced niche alterations promote NSC activation, local oligodendrogenesis, and likely contribute to myelin repair. Multiplexed in situ hybridization-based spatial transcriptomics using the MERSCOPE MERFISH platform was used to analyze coronal adult (P100) CD-1 mouse forebrain sections containing the V-SVZ and corpus callosum, with a 300 gene probeset that included marker genes for relevant cell types, ligands and receptors. We analyzed a region of interest that included the V-SVZ and corpus callosum from four different brains from mice which had been exposed to either a control or cuprizone-rapamycin (cup-rap) protocol (2 control, and 2 cup-rap). Replicates are indicated at the end of each sample name (i.e. Adult_Control_Forebrain_MERFISH_Biol1, Adult_CupRap_Forebrain_MERFISH_Biol1 ).