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

doi:10.1016/j.celrep.2025.115609

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^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

10 Citations (Scopus)

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.

Original language	English
Article number	115609
Journal	Cell Reports
Volume	44
Issue number	5
Early online date	24 Apr 2025
DOIs	https://doi.org/10.1016/j.celrep.2025.115609
Publication status	Published - 27 May 2025

Funding

We would like to thank all members of the Jung laboratory for advice and helpful discussions. We thank the Shahar lab for providing chimeras and the staff of the Weizmann Animal and Flow Cytometry Facilities, as well as M. Tsoory, for help with the CatWalk gait analysis. S.J. is the incumbent of the Henry H. Drake Professional Chair of Immunology. This project was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation; project ID 259373024-TRR 167), an ERA-NET NEURON grant CH-Stroke), and research grants from the Sagol Institute for Longevity Research, the Morris Kahn Institute for Human Immunology, and the Israeli Science Foundation (ISF) (grant #696/21). S.U. is supported by the DFG (project IDs 448121430, 447268119, and 505539112), the Hightech Agenda Bavaria, and an ERC starting grant (project ID 101039438). Whole-brain section imaging was performed on a DFG-funded confocal microscope (project ID 261193037). C.H. is supported by the ERA-NET NEURON grant CH-Stroke and the DFG (project IDs 417284923, 522473931, and 424778381-TRR 295) and by the DZHK (German Center for Cardiovascular Research, partner site Berlin) and the BMBF (German Ministry of Education and Research). P.B. is a scholar of the Einstein Center for Neuroscience Berlin. P.B.-S. and N.W. are supported by the DFG (project ID 424778381-TRR 295). Work in the F.G. lab was supported by grants from the NIH (P30 CA008748, 1R01NS115715-01, 1 R01 HL138090-01, and 1 R01 AI130345-01) and an SRA between Third Rock Ventures and MSKCC, and R.V. was supported by the 2018 AACR-Bristol-Myers Squibb Fellowship for Young Investigators in Translational Immuno-oncology (grant number 18-40-15-VICA).

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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10.1016/j.celrep.2025.115609Licence: CC BY-NC-ND

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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., ... Jung, S. (2025). Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice. Cell Reports, 44(5), Article 115609. https://doi.org/10.1016/j.celrep.2025.115609

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title = "Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice",

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.",

author = "Jung-Seok Kim and S{\'e}bastien Trzebanski and Sun-Hye Shin and Lior Schori and \{Frumer Friedman\}, \{Gal Ronit\} and Ilani, \{Noa Chapal\} and Aditee Kadam and Rocio Vicario and Oliver Aust and Polina Bugaeva and Sylwia Piatek and Ismajli, \{Laura Kate\} and Hoffmann, \{Christian Johannes\} and Marina Scheller and Sigalit Boura-Halfon and Nathali Kaushansky and Ofra Golani and Aryeh Solomon and Zhaoyuan Liu and Lukas Amann and Philipp B{\"o}hm-Sturm and Koch, \{Stefan Paul\} and Nikolaus Wenger and Florent Ginhoux and Marco Prinz and Roi Avraham and Christoph Harms and Frederic Geissmann and Carsten M{\"u}ller-Tidow and Stefan Uderhardt and Ivan Milenkovic and Liran Shlush and Steffen Jung",

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Kim, J-S, Trzebanski, S, Shin, S-H , Schori, L , Frumer Friedman, GR, Ilani, NC, Kadam, A, Vicario, R, Aust, O, Bugaeva, P, Piatek, S, Ismajli, LK, Hoffmann, CJ, Scheller, M, Boura-Halfon, S , Kaushansky, N , Golani, O, Solomon, A, Liu, Z, Amann, L, Böhm-Sturm, P, Koch, SP, Wenger, N, Ginhoux, F, Prinz, M, Avraham, R, Harms, C, Geissmann, F, Müller-Tidow, C, Uderhardt, S, Milenkovic, I, Shlush, L & Jung, S 2025, 'Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice', Cell Reports, vol. 44, no. 5, 115609. https://doi.org/10.1016/j.celrep.2025.115609

TY - JOUR

T1 - Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice

AU - Kim, Jung-Seok

AU - Trzebanski, Sébastien

AU - Shin, Sun-Hye

AU - Schori, Lior

AU - Frumer Friedman, Gal Ronit

AU - Ilani, Noa Chapal

AU - Kadam, Aditee

AU - Vicario, Rocio

AU - Aust, Oliver

AU - Bugaeva, Polina

AU - Piatek, Sylwia

AU - Ismajli, Laura Kate

AU - Hoffmann, Christian Johannes

AU - Scheller, Marina

AU - Boura-Halfon, Sigalit

AU - Kaushansky, Nathali

AU - Golani, Ofra

AU - Solomon, Aryeh

AU - Liu, Zhaoyuan

AU - Amann, Lukas

AU - Böhm-Sturm, Philipp

AU - Koch, Stefan Paul

AU - Wenger, Nikolaus

AU - Ginhoux, Florent

AU - Prinz, Marco

AU - Avraham, Roi

AU - Harms, Christoph

AU - Geissmann, Frederic

AU - Müller-Tidow, Carsten

AU - Uderhardt, Stefan

AU - Milenkovic, Ivan

AU - Shlush, Liran

AU - Jung, Steffen

PY - 2025/5/27

Y1 - 2025/5/27

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/105003226455

U2 - 10.1016/j.celrep.2025.115609

DO - 10.1016/j.celrep.2025.115609

M3 - Article

SN - 2211-1247

VL - 44

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 115609

ER -

Clonal hematopoiesis-associated motoric deficits caused by monocyte-derived microglia accumulating in aging mice

Abstract

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