Aged oligodendrocyte progenitors retain the capacity to respond to an inflammatory insult

Aging is associated with neurodegeneration and progressive disability in people living with multiple sclerosis (MS). Aged oligodendrocyte progenitor cells (OPCs) exhibit slower differentiation and remyelination coupled with upregulation of senescence pathways, both in physiological aging and toxin-mediated murine models. The impact of auto-immune demyelinating environment on young and aged OPCs has not been explored. This study combined a genetic OPC lineage tracing approach in young and middle-aged animals with adoptive transfer of MOG-reactive Th17 T cells to determine how aging influences OPC localization, differentiation and remyelination in an autoimmune environment as well as mature oligodendrocyte survival. Lineage traced OPCs were enriched within lesions compared to non-lesion white matter in both age groups and proliferating OPCs were concentrated at lesion edges. Regardless of age, differentiation of lineage traced OPCs into mature OLs was rare and lowest within lesions. Differentiated OLs were reduced in adoptive transfer, particularly in middle-aged animals, and mature OLs were undergoing cell death within lesions and at meningeal borders. Remyelination was present in lesions from both young and middle-aged animals at this acute timepoint. These findings reveal that an autoimmune inflammatory environment stimulated both young and aged OPCs to proliferate near lesion borders, increase their density lesions, undergo differentiation and remyelinate axons. Differentiated OLs were susceptible to cell death within the lesion environment likely due to cytotoxic MOG-reactive T cells. The rapid and robust response of both OPCs in both age groups suggests that autoimmune-mediated demyelination and the inflammatory lesional environment may directly promote OPC recruitment, proliferation, and differentiation. Identifying cell intrinsic pathways in OPCs that promote OPC and newly formed OL survival during an inflammatory challenge will inform the development of remyelination therapies in MS.