Cell Reports (May 2025)
Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice
- Jung-Seok Kim,
- Sébastien Trzebanski,
- Sun-Hye Shin,
- Lior Schori,
- Gal Ronit Frumer Friedman,
- Noa Chapal Ilani,
- Aditee Kadam,
- Rocio Vicario,
- Oliver Aust,
- Polina Bugaeva,
- Sylwia Piatek,
- Laura Kate Ismajli,
- Christian Johannes Hoffmann,
- Marina Scheller,
- Sigalit Boura-Halfon,
- Nathali Kaushansky,
- Ofra Golani,
- Aryeh Solomon,
- Zhaoyuan Liu,
- Lukas Amann,
- Philipp Böhm-Sturm,
- Stefan Paul Koch,
- Nikolaus Wenger,
- Florent Ginhoux,
- Marco Prinz,
- Roi Avraham,
- Christoph Harms,
- Frederic Geissmann,
- Carsten Müller-Tidow,
- Stefan Uderhardt,
- Ivan Milenkovic,
- Liran Shlush,
- Steffen Jung
Affiliations
- Jung-Seok Kim
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Sébastien Trzebanski
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Sun-Hye Shin
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Lior Schori
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Gal Ronit Frumer Friedman
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Noa Chapal Ilani
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Aditee Kadam
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Oliver Aust
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Exploratory Research Unit, Optical Imaging Centre Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
- Polina Bugaeva
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Sylwia Piatek
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Laura Kate Ismajli
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Christian Johannes Hoffmann
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Marina Scheller
- Department of Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
- Sigalit Boura-Halfon
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Nathali Kaushansky
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Ofra Golani
- MICC Cell Observatory, Department of Life Sciences Core Facilities, Weizmann Institute of Science, Rehovot 7610001, Israel
- Aryeh Solomon
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Zhaoyuan Liu
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China
- Lukas Amann
- Institute of Neuropathology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
- Philipp Böhm-Sturm
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; Charité Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Cluster of Excellence and Charité Core Facility, 7T Experimental MRIs, Berlin, Germany
- Stefan Paul Koch
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; Charité Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, NeuroCure Cluster of Excellence and Charité Core Facility, 7T Experimental MRIs, Berlin, Germany
- Nikolaus Wenger
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Florent Ginhoux
- Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China; Singapore Immunology Network, Agency for Science, Technology & Research, Singapore, Singapore; Translational Immunology Institute, SingHealth Duke-NUS Academic Medical Centre, Singapore, Singapore
- Marco Prinz
- Institute of Neuropathology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany; Signalling Research Centre’s BIOSS and CIBSS, University of Freiburg, 79104 Freiburg, Germany
- Roi Avraham
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Christoph Harms
- Department of Neurology with Experimental Neurology, Center for Stroke Research Berlin and Einstein Center for Neuroscience Berlin, Charité–Universitätsmedizin Berlin, Berlin, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Berlin, Berlin, Germany
- Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
- Carsten Müller-Tidow
- Department of Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg, Heidelberg, Germany
- Stefan Uderhardt
- Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Deutsches Zentrum für Immuntherapie (DZI), Friedrich-Alexander-University Erlangen-Nürnberg (FAU) and Universitätsklinikum Erlangen, Erlangen, Germany; Exploratory Research Unit, Optical Imaging Centre Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), Erlangen, Germany
- Ivan Milenkovic
- Department of Neurology, Medical University Vienna, Wien, Austria
- Liran Shlush
- Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot 7610001, Israel
- Steffen Jung
- Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot 7610001, Israel; Corresponding author
- DOI
- https://doi.org/10.1016/j.celrep.2025.115609
- Journal volume & issue
-
Vol. 44,
no. 5
p. 115609
Abstract
Summary: 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.
Keywords
