Human myeloid ontogeny drives differentiation potential in the brain environment [ATAC-seq]

Microglia, the brain-resident macrophages, play key roles in neurodevelopment and aging, including neurogenesis, synaptic pruning, and myelination. Dysregulated microglia are implicated in various central nervous system (CNS) disorders. Developing safe microglia replacements and eliminating toxic microglia are promising but challenging approaches for treating CNS diseases. Microglia uniquely originate from primitive yolk-sac hematopoiesis, unlike other tissue-resident macrophages that arise from the postnatal bone marrow. Previous studies show that peripheral macrophages fail to adopt microglial characteristics after transplantation. We aim to understand the transcriptional networks underlying the ontological and environmental differences between microglia and peripheral macrophages, which may guide therapeutic strategies. Using human stem cell-derived hematopoietic progenitors (iHPCs) in a humanized mouse model deficient in resident microglia, we demonstrate that iHPCs can replicate the yolk-sac-derived fate of human microglia. We transplanted iHPCs, CD34+ hematopoietic progenitor cells, and umbilical cord blood (UCB)-derived monocytes into murine brains and livers, comparing their differentiation into microglia/macrophages. We found that iHPCs generated more microglia-like cells in the brain compared to CD34+ cells and UCB-derived monocytes, with significant differences in migration and differentiation based on the tissue environment. These findings reveal transcriptional network differences influenced by ontogeny and environment, providing insights for developing microglial-based therapies for CNS disorders.