Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice Journal Article
| Authors: | Kim, J. S.; Trzebanski, S.; Shin, S. H.; Schori, L.; Frumer Friedman, G. R.; Ilani, N. C.; Kadam, A.; Vicario, R.; Aust, O.; Bugaeva, P.; Piatek, S.; Ismajli, L. K.; Hoffmann, C. J.; Scheller, M.; Boura-Halfon, S.; Kaushansky, N.; Golani, O.; Solomon, A.; Liu, Z.; Amann, L.; Böhm-Sturm, P.; Koch, S. P.; Wenger, N.; Bank, N. B.; Ginhoux, F.; Prinz, M.; Avraham, R.; Harms, C.; Geissmann, F.; Müller-Tidow, C.; Uderhardt, S.; Milenkovic, I.; Shlush, L.; Jung, S. |
| Article Title: | Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice |
| Abstract: | Microglia are parenchymal brain macrophages that are established during embryogenesis and form a self-containing cellular compartment that resists seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMΦs) accumulate in the brain of aging mice with distinct topologies, including the nigrostriatum and medulla but not the frontal cortex. Parenchymal MoMΦs adopt bona fide microglia morphology and expression profiles. Due to their hematopoietic stem cell (HSC) derivation, monocyte-derived microglia (MoMg) are unlike yolk-sac-derived cells, targets of clonal hematopoiesis (CH). Indeed, using a chimeric transfer model, we show that the hematopoietic expression of DNMT3AR882H, a prominent human CH variant, renders MoMg pathogenic and promotes motor deficits resembling atypical Parkinsonian disorders. Collectively, we establish that MoMg progressively seed the brain of healthy aging mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can cause brain pathology. © 2025 The Author(s) |
| Keywords: | controlled study; human tissue; somatic mutation; nonhuman; flow cytometry; animal cell; mouse; animal tissue; animal experiment; animal model; gene frequency; aging; monocyte; monocytes; motor dysfunction; functional magnetic resonance imaging; fluorescence activated cell sorting; diffusion weighted imaging; alzheimer disease; immunofluorescence microscopy; microglia; gene expression level; parkinsonism; clonal hematopoiesis; chip; fluorescence intensity; human; male; female; article; resting state network; rna sequencing; hsc; differential gene expression; droplet digital polymerase chain reaction; single cell rna seq; variant allelic frequency; cp: immunology; cp: neuroscience; arch; brain macrophages; ch; dnmt3a r882h; catwalk gait analysis test; motoric deficit |
| Journal Title: | Cell Reports |
| Volume: | 44 |
| Issue: | 5 |
| ISSN: | 2211-1247 |
| Publisher: | Cell Press |
| Date Published: | 2025-05-27 |
| Start Page: | 115609 |
| Language: | English |
| DOI: | 10.1016/j.celrep.2025.115609 |
| PROVIDER: | scopus |
| PUBMED: | 40279248 |
| DOI/URL: | |
| Notes: | The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Source: Scopus |
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