Repeated ablations of mature Tmem10+ oligodendrocytes recapitulates key pathological features of multiple sclerosis with prolonged demyelination.

Managing multiple sclerosis (MS), a chronic, neuroinflammatory and demyelinating disease, remains an unmet medical need. A great obstacle to developing therapeutic interventions altering the disease process is the lack of a suitable disease model recapitulating its core pathologies, especially the process of myelin damage and regeneration against the backdrop of persistent neuroinflammation. Now we report the generation and characterization of a new demyelination/remyelination model with key pathological features of MS through repeated ablations of Tmem10⁺ oligodendrocytes. Using the Tmem10-Cre driver that targets expression of diphtheria toxin receptor (DTR) in Tmem10⁺ (mature myelin-forming) oligodendrocytes, we conducted 3 rounds of Tmem10⁺ oligodendrocyte ablations over the span of 9 weeks in young adult mice by injecting diphtheria toxin (DT). Three rounds of the oligodendrocyte ablation caused prolonged demyelination and axonal injury in the backdrop of chronic neuroinflammation, including gliosis and lymphocyte infiltration. In response to the oligodendrocyte ablations, the proliferation and differentiation of OPCs were accelerated for the regeneration of myelin-forming oligodendrocytes, leading to spontaneous remyelination. This de-/re-myelination model presents a wide "time window" between the onset of demyelination and spontaneous remyelination, which makes it suitable for assessing the efficacy of therapeutic pro-remyelinating agents, as demonstrated by administering Benztropine to this demyelination model.