Somatic mutations reveal the ontogeny of microglia in human aging

Microglia, the resident macrophages of the central nervous system, establish themselves in the brain during embryonic development in mice and can persist throughout life with little input from adult hematopoiesis. The origins of human microglia remain uncertain, although recent research indicates that cells from the bone marrow may contribute to the human microglial population in certain individuals.

To better understand the development of human microglia, researchers designed a method to track the infiltration of marrow-derived cells into the human brain using accumulated somatic mutations. Analyzing the somatic mutations in 20 aged individuals, the study found that marrow-derived cells do indeed enter the human brain across all examined individuals.

Single cell analysis, including tracing the lineage using mitochondrial DNA variants, confirms that these infiltrating cells resemble microglia and can make up a significant portion of the microglial population. This discovery, coupled with an analysis of human cohort data, reveals a protective link between certain types of clonal hematopoiesis and Alzheimer's disease.

The study concludes that a widespread influx of myeloid cells into the healthy human brain contributes to the microglial pool and becomes increasingly common with aging.