Somatic mutations reveal the ontogeny of human microglia
Open accessAbstract
Microglia are the resident hematopoietic cells of the central nervous system 1 . In mice, microglia seed the brain during embryogenesis and can be maintained throughout life with minimal input from adult hematopoiesis 2–4 . The origins of human microglia are less clear, but recent evidence suggests that marrow-derived cells may be able to supplement the human microglial pool in certain individuals 5,6 . Here, to investigate the ontogeny of human microglia, we develop a method that uses the collection of accumulated somatic mutations which uniquely labels each clone of cells to track the infiltration of marrow-derived cells into the human brain. Applying this method to 20 aged individuals, we find evidence of an influx of marrow-derived cells into the brain in all examined individuals. Single cell analysis, including single cell lineage tracing using mitochondrial DNA variants, demonstrates that these infiltrating cells are nearly identical to microglia and can comprise a large fraction of the microglial pool. Analysis of large-scale sequencing cohorts demonstrates a protective association between most types of clonal hematopoiesis and Alzheimer’s disease. In sum, this work uncovers a widespread influx of myeloid cells into the healthy human brain which serves to reinforce the pool of human microglia and becomes common with aging.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Still being checked.
Cited by
Sorted by citations
CSF1R-related leukoencephalopathy: experimental models and potential for treatment
Hume, D. A., & Irvine, K. M. (2026) · Disease Models & Mechanisms · doi:10.1242/dmm.052957
Ledesma‐Corvi, S., Blankers, S. A., McGovern, A. J., Towriss, M., Kim, J. S., Ciernia, A. V., & Galea, L. A. M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.08.31.748388
Hütter, G., Kaymak, D., Williams, P., Hogan, S. A., Ritz, M., Bartolomei, G. D., Zhu, S., Du, S., Melhem, H., Delgado, A. C., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10893390/v1
Gergian, C., Urbanaviciute, P., Wells, P. M., Transfeld, J. L., Askarova, A., Yaa, R. M., Wu, Y., Ziegler, K. C., Nickl, C. K., Pasillas, M. P., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.09.750356
Somatic mosaicism in the brain: linking development, ageing and neurodegeneration
Zhou, Z., & Walsh, C. A. (2026) · Nature Reviews Neurology · doi:10.1038/s41582-026-01268-x
Oon, C. H., Levitt, E. M., Shapiro, D. A., O’Brien, C. A., Davis, M. R., Shestova, O., Axsom, J., Yaqoob, F., Lomeikaitė, V., Koumadorakis, D., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-10963419/v1
Ontogeny and Identity of Tissue Macrophages in Human Aging
Nahrendorf, M. (2026) · JACC Basic to Translational Science · doi:10.1016/j.jacbts.2026.101701
Wong, H. T., Gleason, C., Boylan, A., Adler, M. J., Kosoy, R., Fullard, J. F., Levendosky, E., Hoffman, G. E., Molina, H., Roussos, P., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.09.25.754430
Changjian, W., Furui, W., Yanyu, F., Yü, Y., & Wei, J. (2026) · Experimental Neurology · doi:10.1016/j.expneurol.2026.116058
Shi, H., Zhao, Y., Wei, Z., Yan-jiang, W., & Bu, X.-L. (2026) · Trends in Neurosciences · doi:10.1016/j.tins.2026.09.009
Infection, aging, and innate memory in humans and sea urchins: A macrophage perspective
Madej, M., Pinsino, A., Chu, J., Babarinde, I. A., Tagliabue, A., Italiani, P., & Boraschi, D. (2026) · hLife · doi:10.1016/j.hlife.2026.10.005
Not born in the brain: Bone marrow-derived microglia in human aging
Seo, J., Kim, S., Lee, J., & Yoo, Y. (2026) · Cell stem cell · doi:10.1016/j.stem.2026.10.013
- Authors
- Belk, J. A., Zhang, Y., Shi, Q., Ma, L., Kalluru, R., Enciso, A. M., Reilly, E. E., Weiss, J., Li, R., Eastman, A. E., Womack-Gambrel, N., Paul, D., Chakravarthy, A., Bukhari, S., Bhattacharya, D., Raj, S., Richard, D., Brioschi, S., Chrostek, M. R., Nachun, D. C., Arends, C. M., Gopakumar, J., Tengesdal, I. W., Bynum, A., Mitchell, S., Sandor, K., Vardarajan, B. N., Cobos, I., Born, D. E., Brunet, A., Colonna, M., Vogel, H., Montine, T. J., Hooper, J. E., Weissman, I. L., Keene, C. D., Chang, H. Y., & Jaiswal, S.
- Affiliations
- Stanford Medicine (US)
- Amgen (United States) (US)
- Stanford University (US)
- Washington University in St. Louis (US)
- NewYork–Presbyterian Hospital (US)
- University of Washington (US)
- Corresponding author
- Belk, Julia A.
- ORCID
- Belk, Julia A.
- Zhang, Yaowen
- Shi, Quanming
- Enciso, Alejandro Medina
- Reilly, Emily E.
- Weiss, Jacob
- Li, Rui
- Eastman, Anna E.
- Paul, Debasmita
- Chakravarthy, Arnav
- Bukhari, Syed
- Bhattacharya, Dipabarna
- Richard, Daniel
- Brioschi, Simone
- Chrostek, Matthew R.
- Nachun, Daniel C.
- Arends, Christopher M.
- Gopakumar, Jayakrishnan
- Tengesdal, Isak W.
- Mitchell, Shaneice
- Sandor, Katalin
- Vardarajan, Badri N.
- Cobos, Inma
- Born, Donald E.
- Brunet, Anne
- Colonna, Marco
- Vogel, Hannes
- Montine, Thomas J.
- Hooper, Jody E.
- Weissman, Irving L.
- Keene, C. Dirk
- Chang, Howard Y.
- Jaiswal, Siddhartha
- Venue
- bioRxiv (Cold Spring Harbor Laboratory)
- Publisher
- openRxiv
- Published
- 2026-05-20
- OpenAlex
- W7161829625
- Cited by
- 3
- References
- 0
- Citations by year
- 2026: 3
- Type
- posted content
- Language
- en
- Open access
- green
- doi.org
- Locations
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (submittedVersion)
- Funders
- U.S. Department of Defense (W81XWH-21-S-TBIPH2, W81XWH-21, W81XWH, DoD W81XWH-21-S-TBIPH2)
- Howard Hughes Medical Institute (SCR_017788)
- National Institutes of Health (SCR_017788, W81XWH, AG066509, AG066567)
- Charles F. and Joanne Knight Alzheimer Disease Research Center, Washington University in St. Louis
- National Institute on Aging (U19AG066567, U24AG072458, P30AG066509, U19AG060909)
- National Heart, Lung, and Blood Institute (DP2HL157540)
- National Institute of Neurological Disorders and Stroke (U24NS133945, U24NS133949, U01NS137484, U01NS137500)
- Topics
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Keywords
- microglia, somatic mutations, clonal hematopoiesis, myeloid cell infiltration, brain aging, Alzheimer's disease, mitochondrial DNA variants, single-cell lineage tracing, human brain
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
