The study investigates the role of microglia/macrophages in the remyelination process following central nervous system (CNS) demyelination. It finds that a switch from an M1 to an M2-dominant response occurs within microglia and peripherally-derived macrophages as remyelination begins. M2-conditioned media enhances oligodendrocyte differentiation in vitro and impairs it in vivo following intra-lesional M2 depletion. M2 densities are increased in lesions of aged mice with enhanced remyelination and in multiple sclerosis (MS) lesions. Blocking M2-derived activin-A inhibits oligodendrocyte differentiation during remyelination. These findings suggest that M2 polarization is essential for efficient remyelination and identify activin-A as a novel therapeutic target for CNS regeneration.The study investigates the role of microglia/macrophages in the remyelination process following central nervous system (CNS) demyelination. It finds that a switch from an M1 to an M2-dominant response occurs within microglia and peripherally-derived macrophages as remyelination begins. M2-conditioned media enhances oligodendrocyte differentiation in vitro and impairs it in vivo following intra-lesional M2 depletion. M2 densities are increased in lesions of aged mice with enhanced remyelination and in multiple sclerosis (MS) lesions. Blocking M2-derived activin-A inhibits oligodendrocyte differentiation during remyelination. These findings suggest that M2 polarization is essential for efficient remyelination and identify activin-A as a novel therapeutic target for CNS regeneration.