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Updated: Jul 4, 2026
Bone Marrow-derived Macrophage Production
Published on: November 22, 2013
Brain-engrafted monocyte-derived macrophages from blood and skull-bone marrow exhibit distinct properties
Siling Du1, Feiya Ou2, Antoine Drieu3
1Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO, USA; Brain Immunology and Glia (BIG) Center, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
Abstract:
Microglia arise from yolk sac progenitors and are thought to persist throughout life with minimal input from adult hematopoiesis. However, whether brain-engrafted monocyte-derived macrophages (MDMs) exist at homeostasis and during turnover and how they function relative to yolk-sac-derived microglia (YSMs) remain unsettled. Here, we combine lineage tracing, pharmacological microglia depletion, and multi-omics profiling to define the ontogeny, identity, and function of brain parenchymal macrophages. Despite sharing the parenchymal milieu, MDMs display transcriptional and epigenetic landscapes distinct from YSMs. Fate-mapping reveals that brain-engrafted MDMs transiently express CD206, echoing a developmental stage of microglial precursors. MDM engraftment and polarization are modulated by interleukin (IL)-34 and C-C chemokine receptor 2 (CCR2). Furthermore, parabiosis and skull-flap transplantation reveal that both blood and skull marrow supply the niche, yielding origin-biased MDM states. Functionally, MDM engraftment enhances cuprizone-mediated demyelination. Together, our study defines the origins, molecular features, and context-dependent roles of brain parenchymal macrophages across homeostasis, turnover, and central nervous system (CNS) pathology.
Insights
This study reveals that monocyte-derived macrophages (MDMs) exist in the brain alongside microglia. These MDMs have distinct molecular features and influence central nervous system (CNS) pathology, particularly demyelination.
Area of Science:
- Neuroimmunology
- Cellular and Molecular Neuroscience
- Hematopoiesis
Background:
- Microglia, the brain's resident immune cells, originate from yolk sac progenitors and were traditionally considered long-lived with minimal adult hematopoietic contribution.
- The presence, function, and distinct identity of monocyte-derived macrophages (MDMs) within the brain parenchyma at homeostasis and during turnover remain poorly understood relative to yolk-sac-derived microglia (YSMs).
Purpose of the Study:
- To define the ontogeny, molecular identity, and functional roles of brain parenchymal macrophages, including both YSMs and infiltrating MDMs.
- To investigate how MDMs interact with the microglial niche and contribute to central nervous system (CNS) pathology.
Main Methods:
- Lineage tracing techniques to track cell origins.
- Pharmacological depletion of microglia to assess compensatory mechanisms.
- Multi-omics profiling (transcriptional and epigenetic) to compare macrophage populations.
- Parabiosis and skull-flap transplantation models to study cell sourcing and niche dynamics.
Main Results:
- Monocyte-derived macrophages (MDMs) exhibit distinct transcriptional and epigenetic profiles compared to yolk-sac-derived microglia (YSMs), despite sharing the brain environment.
- Engrafted MDMs transiently express CD206, mirroring a developmental microglial precursor stage, and their engraftment/polarization are influenced by IL-34 and CCR2.
- Both blood and skull marrow contribute to the macrophage pool, leading to origin-biased MDM states within the CNS niche.
- MDM engraftment was found to exacerbate cuprizone-induced demyelination, highlighting their functional impact in CNS pathology.
Conclusions:
- The study delineates the distinct origins, molecular characteristics, and functional contributions of brain parenchymal macrophages, including MDMs and YSMs.
- MDMs play context-dependent roles in CNS homeostasis, turnover, and pathology, notably influencing demyelination processes.
- This research refines our understanding of brain immune cell dynamics and their implications for neurological diseases.
