Brain wide engraftment of human monocytes induces neurodegeneration and cognitive dysfunction.

Transplantation of peripherally derived myeloid cells in combination with microglia depletion is increasingly being examined as a potential therapy for various neurological disorders.1-9 However, primitive yolk sac derived microglia and definitive bone marrow derived monocytes and macrophages exhibit distinct developmental ontogenies.10-12 Important differences between murine and human myeloid cells further obscure the translational potential of this approach.8,13-16 To understand the impact of peripherally derived human myeloid cells on brain function and health we utilized a xenotolerant mouse model that lacks endogenous microglia. Using a combination of spatial sequencing, proteomics, histological, biochemical, and machine learning behavioral approaches we then examined the impact of brain wide engraftment of human induced pluripotent stem cell-derived microglia, which mimic the primitive ontogeny of microglia, in comparison to definitive bone marrow derived monocytes. Here we show that engraftment of human monocytes, but not microglia, promotes a chronic proinflammatory state associated with astrogliosis, demyelination, and synaptic and neuronal loss. These robust changes in myeloid cell activation state and brain homeostasis are in turn accompanied by significant impairments in cognitive function. Together with the accompanying study by Wang and colleagues, we demonstrate the critical impact of myeloid cell ontogeny on neuronal health and function, providing important implications for the rapidly progressing development and translation of brain-wide microglial replacement therapies.1-5.