Delayed Oligodendrocyte Progenitor Cell Recruitment and Maturation in Large Volume Demyelination

Abstract

Remyelination-inducing therapies have the potential to restore neurologic function and prevent progression in multiple sclerosis (MS). However, preclinical therapies capable of driving oligodendrocyte differentiation and enhancing remyelination in murine models have not yet yielded meaningful clinical improvement. These setbacks suggest that small animal models may be inadequate for the development and identification of promising regenerative therapies. Unlike MS, rodent models of demyelination undergo highly efficient remyelination, have typically very small volumes and exhibit abundant oligodendrocyte recruitment rapidly following demyelination. We hypothesized that oligodendrocyte progenitor cell (OPC) recruitment becomes rate-limiting as lesion volume increases leading to a failure of oligodendrocyte differentiation and endogenous remyelination. In this study, we utilized lysolecithin injection into the large white matter tracts of the rabbit to create demyelinated lesions that have cross-sectional areas 20-fold larger than those previously reported in mice, and volumes 8-fold larger. Unlike rodent lesions which show robust supernumerary OPC recruitment (representing a 3-10 fold increase in Olig2⁺ cell density), recruitment in the rabbit never exceeds normal levels. Importantly, the density of mature CC1⁺ oligodendrocytes failed to return to NAWM levels by 56 dpl and the percentage of differentiated oligodendrocytes drastically lagged behind that of rodent lesions. These results suggest that as lesion volume increases the requirement for increased OPC proliferation and migration becomes limiting. As oligodendrocyte differentiation from human OPCs is dependent on the local density of progenitors, the reduced density of progenitors in large lesions may contribute to failed differentiation and remyelination. Together, we show that large volume demyelination in the white matter of the rabbit recapitulates several key features of human MS lesions, and represents an important preclinical model for the assessment of remyelination therapies in human demyelinating disease.