Immune cells called microglia act as the brain’s cleanup crew, patrolling the networks, engulfing invaders, and pruning connections to maintain brain health.1 Intrigued by the cells’ diverse roles, researchers have been trying to understand how microglia emerge and find their place in the brain.
More than a decade ago, mouse experiments revealed that microglia develop from yolk sac-derived progenitor cells during gestation and that the animals’ brains retain the cells throughout their lives without input from blood cells.2 While researchers found a similar yolk sac-origin for human microglia, early evidence challenged the view that peripheral blood cells do not contribute to the microglial pool over time.3
Now, providing further evidence, a team from Stanford University found that bone marrow-derived cells regularly migrate to the human brain during aging and contribute to the microglial population.4 The findings, published in Nature, pave the way to potentially harness this process to deliver therapeutics into the brain.
The human brain becomes intertwined with the blood during aging, as circulating blood cells gradually replace brain-resident microglia.
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“[This] is a tour de force study,” said Miriam Merad, an immunologist and oncologist at the Icahn School of Medicine at Mount Sinai, who demonstrated the developmental origins of tissue-resident macrophages and who was not associated with the study. “It’s a very interesting paper using a very interesting technology. I’m very excited about the study.”
Clonal Mutations Help Trace Cell Lineages
The first clue that blood cells might be moving to the brain to become microglia emerged when the study authors were studying individuals with clonal hematopoiesis, wherein mutations in a blood progenitor cell pass on to its progeny, resulting in a significant proportion of circulating blood cells with the same mutation. “We started finding those same [blood cell] mutations also in the brain and in the microglia of some of these people,” said study coauthor Julia Belk, a postdoctoral researcher in immunologist Siddhartha Jaiswal’s lab at Stanford University.5
Wanting to understand whether this influx of immune cells occurred in the broader aging population, Jaiswal and Belk joined forces with Stanford University physician and molecular biologist Howard Chang. They started by developing a method to identify and track cells that emerge in the bone marrow.
Cells acquire mutations and pass these on to their progeny. So, Belk and her colleagues hypothesized that if bone marrow-derived cells carrying mutations infiltrated the brain, over time, brain cells would show the same mutations.
In the new study, the researchers analyzed blood samples from 16 people to identify mutations using whole genome sequencing. DNA sequencing of the respective individuals’ postmortem brain tissue samples revealed the presence of the same mutations, suggesting that bone marrow-derived blood cells infiltrated the brain in each case.
“[This methodology] opens up a new path of human studies,” said Merad, adding that investigating the origin and development of cell lineages “now becomes possible thanks to this type of method.”
Infiltrating Peripheral Cells Replenish the Microglial Pool
The researchers next carried out single-cell analyses to identify the brain cell type carrying the blood cell-derived mutations and found that the cells resembled microglia. When the researchers compared the mutation-carrying cell fraction to the total microglia pool, they observed that more than 26 percent of the microglia consisted of infiltrating cells. Moreover, this pool was the highest among older individuals, indicating that microglia replacement increases with age.
Julia Belk is an immunologist at Stanford University.
Don Feria/AP Images for HHMI
“The brain is typically thought of as quite closed off to external inputs [and] external cells,” said Belk. “[But] at some point in aging, at least some of the cells are coming from the peripheral blood.”
She noted that mouse brains differ significantly from human brains in this aspect, which underscores the importance of rethinking animal models for brain disorders. “It's going to be very important to have good mouse models that recapitulate this aspect of human biology,” she explained.
Despite the significance of the findings, Merad was not entirely surprised to see bone marrow-derived cells infiltrating the brain. Tissue-resident immune cells deplete with age in mice, said Merad, and researchers had hypothesized that circulating blood cells replace them. “I anticipated that this would be even more accentuated in humans because [we] have a longer lifespan,” she explained.
Engineered Bone Marrow-Derived Cells to Deliver Brain Therapies
Finally, Belk and her colleagues investigated whether there was an association between the blood cell-derived mutations and Alzheimer’s disease. By analyzing whole genome sequences of blood cells of thousands of people with and without Alzheimer’s disease, the researchers found that those with blood cell clones arising from mutated progenitor and stem cells showed a lower risk of the disease. While the researchers had previously found that one type of clonal hematopoiesis is protective of Alzheimer’s disease, the current findings are more generalizable to a broader population with any type of clonal hematopoiesis, Belk explained.5
“That is a very exciting result,” said Merad. “The question is, can we utilize the delivery of cells with that molecular phenotype that could potentially help with neural protection? I think absolutely yes.” Zooming out from neurodegenerative diseases, Merad believes that blood cells with mutations that drive clonal hematopoiesis could be used as a way to deliver therapies for dementia, glioblastomas, and even psychiatric diseases to the brain.
“I would love to use this to develop immune cell therapies for the brain so that we can think about engineering these peripheral cells to do useful things or even deliver other molecules into the brain,” agreed Belk. However, she noted that blood cells infiltrate the brain at a very old age, which could potentially limit the utility of harnessing this process for pediatric diseases.
Despite this, Belk is excited about the findings. “Just the fact that there [are] processes going on in the human brain, honestly, in the human body in general, that we just had no idea about…that really surprised me and has been very exciting,” she said.
- Colonna M, Butovsky O. Microglia function in the central nervous system during health and neurodegeneration. Annu Rev Immunol. 2017;35:441-468.
- Ginhoux F, Merad M. Microglia arise from extra-embryonic yolk sac primitive progenitors. Med Sci (Paris). 2011;27(8-9):719-724.
- Bian Z, et al. Deciphering human macrophage development at single-cell resolution. Nature. 2020;582(7813):571-576.
- Belk A, et al. Somatic mutations reveal the ontogeny of microglia in human aging. Nature. 2026
- Bouzid H, et al. Clonal hematopoiesis is associated with protection from Alzheimer's disease. Nat Med. 2023;29(7):1662-1670.
