A human-induced pluripotent stem cell-derived spheroid model to investigate myelin injury and repair.

There are no currently approved therapies that promote new myelin formation after myelin damage, which can, in part, be attributed to a lack of reliable systems that can reproducibly model these processes. Here we engineered a human iPSC-derived spheroid model enriched with mature, myelinating oligodendrocytes and functionally reactive microglia. This model enables the study of human central nervous system remyelination after a demyelinating insult by recapitulating processes of myelin damage and repair. These include myelin fragmentation, microglial reactivity and phagocytosis of myelin debris, oligodendrocyte generation and differentiation, and axonal ensheathment with newly formed myelin. We show that newly generated oligodendrocytes contribute to remyelination, and use ultrastructural quantification to demonstrate that remyelinated axons are ensheathed by thinner myelin after injury. Altogether, we provide a model to interrogate otherwise inaccessible aspects of human myelin biology relevant to multiple sclerosis, providing mechanistic insights into disease pathways and a platform for drug screening.