This study investigates the role of M2 microglia/macrophages in the process of remyelination following central nervous system (CNS) demyelination. The research reveals that a shift from an M1 to an M2 dominant response occurs in microglia and peripherally-derived macrophages as remyelination begins. M2 cells are shown to enhance oligodendrocyte differentiation in vitro and impair it in vivo when their numbers are reduced. M2 cell density is increased in lesions of aged mice that show enhanced remyelination when parabiont with a younger animal, and in multiple sclerosis (MS) lesions that typically show remyelination. Blocking M2-derived activin-A inhibits oligodendrocyte differentiation during remyelination in cerebellar slice cultures. The study concludes that M2 polarization is essential for efficient remyelination and identifies activin-A as a novel therapeutic target for CNS regeneration. The findings suggest that M2 microglia/macrophages drive oligodendrocyte differentiation during remyelination and that this is an essential part of an effective remyelination response. The study also highlights activin-A as a promising novel therapeutic target for CNS myelin regeneration.This study investigates the role of M2 microglia/macrophages in the process of remyelination following central nervous system (CNS) demyelination. The research reveals that a shift from an M1 to an M2 dominant response occurs in microglia and peripherally-derived macrophages as remyelination begins. M2 cells are shown to enhance oligodendrocyte differentiation in vitro and impair it in vivo when their numbers are reduced. M2 cell density is increased in lesions of aged mice that show enhanced remyelination when parabiont with a younger animal, and in multiple sclerosis (MS) lesions that typically show remyelination. Blocking M2-derived activin-A inhibits oligodendrocyte differentiation during remyelination in cerebellar slice cultures. The study concludes that M2 polarization is essential for efficient remyelination and identifies activin-A as a novel therapeutic target for CNS regeneration. The findings suggest that M2 microglia/macrophages drive oligodendrocyte differentiation during remyelination and that this is an essential part of an effective remyelination response. The study also highlights activin-A as a promising novel therapeutic target for CNS myelin regeneration.