Hematopoietic stem cell transplant is the gold standard for treatment of globoid cell leukodystrophy, also called Krabbe disease. Aisenberg et al. define the molecular signature of disease-associated macrophages (globoid cells) and demonstrate that brain-specific high-efficiency macrophage replacement in the twitcher model of Krabbe disease improves neuropathology, macrophage dysfunction, and survival.

Replacing brain macrophages holds substantial therapeutic promise but remains challenging. Bastos et al. uncover the requirements for monocytes to replace microglia and border-associated macrophages. They show that monocyte ontogeny shapes brain macrophage identity, with fetal monocytes acquiring a true microglial state. Using xenotransplantation and Alzheimer’s patient data, they identify human monocyte-derived microglia. These findings are important for microglia replacement therapies.