Brain-Engrafted Monocyte-derived Macrophages from Blood and Skull-Bone Marrow Exhibit Distinct Identities from Microglia

作者：Siling Du, Antoine Drieu, Yumeng Cheng, Steffen E. Storck, Justin Rustenhoven, Tornike Mamuladze, Bishan Bhattarai, Simone Brioschi, Khai M. Nguyen, Feiya Ou, Jay Cao, Patrick Fernandes Rodrigues, Igor Smirnov, David G. DeNardo, Florent Ginhoux, Marina Cella, Marco Colonna, Jonathan Kipnis · 发表于：bioRxiv (Cold Spring Harbor Laboratory) · 年份：2024 · DOI：10.1101/2024.08.08.606900 · 被引用次数：12 · 研究领域：Neuroinflammation and Neurodegeneration Mechanisms、Immune cells in cancer、Extracellular vesicles in disease

SUMMARY Microglia are thought to originate exclusively from primitive macrophage progenitors in the yolk sac (YS) and to persist throughout life without much contribution from definitive hematopoiesis. Here, using lineage tracing, pharmacological manipulation, and RNA-sequencing, we elucidated the presence and characteristics of monocyte-derived macrophages (MDMs) in the brain parenchyma at baseline and during microglia repopulation, and defined the core transcriptional signatures of brain-engrafted MDMs. Lineage tracing mouse models revealed that MDMs transiently express CD206 during brain engraftment as CD206 + microglia precursors in the YS. We found that brain-engrafted MDMs exhibit transcriptional and epigenetic characteristics akin to meningeal macrophages, likely due to environmental imprinting within the meningeal space. Utilizing parabiosis and skull transplantation, we demonstrated that monocytes from both peripheral blood and skull bone marrow can repopulate microglia-depleted brains. Our results reveal the heterogeneous origins and cellular dynamics of brain parenchymal macrophages at baseline and in models of microglia depletion.