Studying the effect of Clonal Hematopoiesis on Brain Function through Monocyte- Derived Microglia
2Department of Medicine, Hematology, Oncology and Rheumatology, University Hospital Heidelberg
3Department of Internal Medicine 3-Rheumatology and Immunology, Friedrich-Alexander-University Erlangen-Nrnberg and Universittsklinikum Erlangen
4Department of Neurology, Medical University Vienna
5Departments of Immunology and Molecular Cell Biology, Weizmann Institute of Science
Fate mapping studies in animals have shown that microglia (Mg), the brain resident macrophages, are yolk sac (YS) -derived and established early in embryogenesis. Furthermore, analysis of adult mice has led to the prevailing dogma that this cellular compartment subsequently resists seeding with cells derived from definitive hematopoiesis. Rather, monocyte-derived macrophages (MoMΦ) were shown to colonize the brain only when Mg are compromised, while maintaining distinct epigenomes and gene expression compared to YS-derived Mg (YS-Mg). Recent work from our group, based on fate-mapping of monocytes, challenges this paradigm. Specifically, we revealed an age-related accumulation of MoMΦ in naïve, unchallenged mice in distinct brain regions excluding the frontal cortex. Notably, single-cell transcriptome analysis revealed that parenchymal monocyte-derived Mg (MoMg) adopt bona fide microglial expression profiles.
Due to their HSC derivation, MoMg are subject to somatic mutations associated with clonal hematopoiesis (CH), a phenomenon linked with hematologic malignancies, as well as cardiovascular and cerebrovascular disorders. Using a BM transfer model, we demonstrate that hematopoietic expression of DNMT3AR882H—a prominent human clonal hematopoiesis (CH) mutation—induces motor deficits resembling atypical Parkinsonian disorders, mediated by monocyte-derived macrophages (MoMg).
To better model the impact of CH on the CNS through MoMg, we are in the process of developing a system that more closely mimics human CH. By employing localized leg irradiation, we minimize overall irradiation exposure while achieving lower levels of chimerism that align with the frequencies of CH mutations observed in humans. Our preliminary results confirm that DNMT3AR882H-harboring cells exhibit greater expansion in the blood compared to wild-type cells.
Collectively, these findings establish in a mouse model that MoMg progressively seed the brain of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology.