Global human myeloid replacement with peripheral progenitors induces interferonopathy and neurodegeneration

Microglia, the brain's resident macrophages, arise from yolk sac hematopoietic progenitor cells (HPCs) that migrate into the brain during early embryonic development and differentiate in response to microenvironment-specific signals. The resulting spatial and stage-specific programs of gene expression enable microglia to function as key modulators of diverse homeostatic processes that include synaptic pruning, myelination, and neurogenesis throughout the lifespan. Dysregulation of these core microglia functions has been linked to numerous neurodevelopmental and neurodegenerative diseases. Although normally a closed niche, studies in mice indicate that peripheral monocytes, originating from hematopoietic stem cells (HSCs), can infiltrate the brain in circumstances in which the blood brain barrier is disrupted, with context-dependent protective or detrimental consequences. A major unanswered question with significant implications for therapy of CNS diseases driven by microglia dysfunction is the extent to which human HSC-derived cells can adopt microglia-like phenotypes that would allow them to restore brain homeostasis by replacement of pathologic HPC-derived microglia. To address this question, we directly compared the differentiation potential of primary human microglia, human iPSC-derived HPCs and human HSCs in the brain utilizing a murine xenotransplantation model. HSCs and monocytes were capable of differentiating into microglia like cells in this model, they also acquired a strong interferon, phagocytic, and antigen presenting phenotype distinct from engrafted primary human microglia and HPC-derived cells. Analyses of the epigenetic landscapes of the engrafted HPC and HSC-derived cells enabled identification of the transcription factors networks underlying ontogeny-specific brain myeloid fates. Ultimately, human peripheral myeloid cells in the CNS led to astrogliosis, myelin fragmentation and synaptic loss. These findings reveal transcriptional network differences influenced by ontogeny, and together with the accompanying study by Davtvan and colleagues provide critical insights for developing human microglial or bone marrow transplant-based therapies for CNS disorders.