Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice
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 DNMT3A<sup>R882H</sup>, 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.
Authors
- Ofra Golani (ORCID: https://orcid.org/0000-0002-9793-236X)
- Noa Chapal Ilani
- Marco Prinz (ORCID: https://orcid.org/0000-0002-0349-1955)
- Carsten Müller‐Tidow (ORCID: https://orcid.org/0000-0002-7166-5232)
- Sébastien Trzebanski (ORCID: https://orcid.org/0000-0002-0647-6814)
- Christian J. Hoffmann (ORCID: https://orcid.org/0000-0003-0861-2418)
- Liran I. Shlush (ORCID: https://orcid.org/0000-0002-3700-270X)
- Rocío Vicario (ORCID: https://orcid.org/0000-0002-7894-5261)
- Gary S. Friedman (ORCID: https://orcid.org/0000-0003-2479-328X)
- Stefan Uderhardt (ORCID: https://orcid.org/0000-0002-2489-2109)
- Florent Ginhoux (ORCID: https://orcid.org/0000-0002-2857-7755)
- Nathali Kaushansky (ORCID: https://orcid.org/0000-0003-1845-6586)
- Sylwia Piątek (ORCID: https://orcid.org/0009-0004-4772-8442)
- Lior Schori
- Oliver Aust
- Roi Avraham (ORCID: https://orcid.org/0000-0002-9098-3885)
- Nikolaus Wenger (ORCID: https://orcid.org/0000-0002-0965-7530)
- Marina Scheller (ORCID: https://orcid.org/0000-0001-6108-0831)
- Lukas Amann (ORCID: https://orcid.org/0000-0002-8363-373X)
- Aditee Kadam
- Sigalit Boura‐Halfon (ORCID: https://orcid.org/0009-0000-9172-0051)
- Polina Bugaeva (ORCID: https://orcid.org/0000-0001-8745-2568)
- Frédéric Geissmann (ORCID: https://orcid.org/0000-0001-5029-2468)
- Steffen Jung (ORCID: https://orcid.org/0000-0003-4290-5716)
- Christoph Harms (ORCID: https://orcid.org/0000-0002-2063-2860)
- Philipp Boehm‐Sturm (ORCID: https://orcid.org/0000-0001-8777-4823)
- Ivan Milenković (ORCID: https://orcid.org/0000-0003-1431-9031)
- Sun‐Hye Shin (ORCID: https://orcid.org/0009-0008-8950-3822)
- Jung‐Seok Kim (ORCID: https://orcid.org/0000-0003-0284-1658)
- Stefan Koch (ORCID: https://orcid.org/0000-0001-6606-6369)
- Aryeh Solomon (ORCID: https://orcid.org/0000-0001-7647-5465)
- Zhaoyuan Liu
- Laura Kate Ismajli
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- SingHealth (SG)
- University of Freiburg (DE)
- Friedrich-Alexander-Universität Erlangen-Nürnberg (DE)
- Shanghai Jiao Tong University (CN)
- Heidelberg University (DE)
- University Medical Center Freiburg (DE)
- University Hospital Heidelberg (DE)
- Humboldt-Universität zu Berlin (DE)
- Universitätsklinikum Erlangen (DE)
- German Centre for Cardiovascular Research (DE)
- Einstein Center for Neurosciences Berlin (DE)
- Weizmann Institute of Science (IL)
- Medical University of Vienna (AT)
- Charité - Universitätsmedizin Berlin (DE)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-04-23
- DOI
- https://doi.org/10.1016/j.celrep.2025.115609
- Citations
- 15
- Primary Topic
- Neuroinflammation and Neurodegeneration Mechanisms
- Type
- article
- Field-Weighted Citation Impact
- 12.63