Oligodendrocyte Progenitor Cell Transcriptome in White Matter Stroke

Tissue progenitors maintain the integrity of organ systems through aging and stress. The brain’s white matter regions experience ischemic lesions and age-dependent degeneration. Brain white matter contains progenitors, oligodendrocyte precursor cells (OPCs), which can repair some insults. The response of OPCs to white matter ischemia and aging is not known. We characterized the response of OPCs to white matter stroke using OPC reporter mice, cell migration tracking, OPC specific RNA sequencing, and mechanistic studies in candidate biochemical pathways in the aged brain. White matter stroke induces initial proliferation of local OPCs but blocks differentiation, shunting a portion into astrocytes. Candidate signaling pathways for this differentiation block including novel interactions of inhibin and matrilin-2 and new roles of NgR1 ligands following white matter stroke. Stroke induces inhibin expression in astrocytes and downregulates OPC matrilin-2 that contributes into OPC differentiation block. Antagonism of NgR1 ligands promotes OPC differentiation by attenuating the OPC astrocytic transformation and enhances functional recovery from stroke in aged animals.