Human myeloid ontogeny determines inflammatory identity and neurodegenerative potential

ABSTRACT: Microglia, the resident macrophages of brain, 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 the CNS is normally a closed myeloid niche, recent evidence suggests that aging involves loss of yolk sac–derived microglia and emergence of peripheral myeloid-derived populations, highlighting the need to define whether human hematopoietic stem cell (HSC)-derived myeloid cells can acquire microglia-like identities and sustain brain homeostasis. To address this, we compared yolk sac–lineage human primary microglia and iPSC-derived hematopoietic progenitor cell (HPC)-derived myeloid cells with peripheral-lineage human HSC- and monocyte-derived myeloid cells in a humanized murine xenotransplantation model. Peripheral-lineage cells efficiently populated the brain and acquired microglia-like features but remained transcriptionally and epigenetically distinct from HPC-derived brain myeloid cells. Compared with HPC-derived cells, peripheral myeloid cells showed heightened interferon signaling, phagocytic programs, and antigen-presentation signatures. Integrative epigenomic analyses identified ontogeny-dependent transcription factor networks underlying these divergent brain myeloid states and correlated with aging related infiltrative myeloid populations. Functionally, global replacement with HSC-derived myeloid cells was associated with astrogliosis, myelin fragmentation, and synaptic loss, indicating neurodegenerative consequences. Together with the accompanying study by Davtyan and colleagues, these findings demonstrate that human peripheral progenitors can partially adopt microglia-like phenotypes but retain pro-inflammatory programs that promote neurodegeneration after global myeloid replacement. This work provides insight into age-associated myeloid replacement in the human brain and informs the risks and therapeutic potential of microglial replacement and bone marrow transplant–based strategies for CNS disorders.

ORGANISM(S): Homo sapiens

PROVIDER: GSE343488 | GEO | 2026/08/12

REPOSITORIES: GEO