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Abstract

Demyelination, which impairs electrical signal transmission in the nervous system, occurs during aging and following spinal cord injury (SCI). Chronically, it contributes to axonal damage and degeneration. The functional relevance of remyelination following SCI in aging individuals remains poorly understood. I first employed a fate-mapping approach in uninjured young (3 month) and aged (18 month) mice genetically modified to express green fluorescent protein in platelet-derived growth factor receptor alpha (PDGFRα)-positive cells, a marker for oligodendrocyte progenitor cells (OPCs). Contrary to the expectation, aging did not affect the density of PDGFRα+ or oligodendrocyte (OL), nor did it influence baseline locomotor or cognitive function. We then examined how remyelination failure impacts recovery in aged mice following moderate thoracic SCI. We deleted the myelin regulatory factor (Myrf) from PDGFRα+ cells, thereby inhibiting OPC differentiation into OLs and halting new OL formation. While PDGFRα+ cell density and proliferation remained unchanged in Myrf knockout mice, OL accumulation was significantly reduced in both young (3-5 month) and aged (15-18 month) cohorts. Following SCI, Myrf ICKO mice had fewer total axons and more unmyelinated axons than controls and displayed greater functional deficits in aged mice. Notably, young mice exhibited no behavioral functional deficits despite impaired remyelination, while aged Myrf ICKO mice showed pronounced locomotor and cognitive impairments. Together, these findings support remyelination therapies as a promising strategy for older individuals.