The central nervous system (CNS) maintains a close relationship with the immune cells, mainly border-associated macrophages (BAMs) and microglia. They play an important role in homeostasis and neuroprotection. Microglia are long-lived and self-renewing cells. BAMs are heterogeneous and continuously renewed by bone marrow-derived monocytes. Under steady-state conditions, circulating monocytes cannot replace microglia and BAMs. However, pathological situations or experimental interventions may disrupt these dynamics.
The aim of this study is to examine how BM-derived monocytes may engraft and replace embryonic brain-resident macrophages after radiation-induced niche clearance or pharmacologic depletion in mouse models. The objective is to understand macrophage ontogeny better and develop therapeutic strategies for brain macrophage replacement, with a particular focus on Alzheimer’s disease. It also compares the functional and transcriptional characteristics of the engrafted monocyte-derived cells to their native forms and examines molecular identity, clonal persistence, and long-term integration. It assesses the capacity of the fetal liver (FL) monocytes and human CD14+ monocytes from adult blood and cord to develop microglia-like cells in vivo. This gives information about the therapeutic benefits for the CNS system.
After depleting microglia with the PLX3397 (a CSF1R inhibitor), researchers discovered that Lob BAMs (found in leptomeningeal and perivascular spaces) were efficiently replaced by monocytes. Brain parenchymal microglia were mostly intolerant to BM-derived cell integration because of the rapid regeneration of remaining embryonic microglia. When microglial proliferation was inhibited by CSF1R deletion or targeted irradiation, BM-derived monocytes entered the brain and differentiated into microglia-like cells (Mo-Microglia), exhibiting long-term survival and clonal growth. Monocyte engraftment was more effective in newborns because of the lack of competition from endogenous microglia, which led to a steady coexistence of native and Mo-Microglia. Transcriptomic investigations showed that Mo-Microglia and monocyte-derived Lo BAMs had different gene expression patterns in comparison to their embryonic counterparts, even after prolonged residence.
Embryonic macrophages and monocyte-derived cells have different developmental and epigenetic characteristics, which allow them to differentiate into microglia-like cells. In contrast to adult bone marrow monocytes, fetal liver monocytes have the capacity to differentiate into microglial cells. Cord blood monocytes exhibit more engraftment than the adult monocytes and differentiate into LYVE1⁺ BAM-like and KCNQ3⁺ Mo-Microglia cells. These human-derived Mo-Microglia did not express SALL1+, which shows incomplete identity acquisition. In patients with Alzheimer’s disease, there are the same Mo-Microglia-like clusters in the brain tissue, where they associate with amyloid plaques and may exacerbate disease severity.
This study only examined the delivery of monocytes from the peripheral BM cells to the mouse brain by intracerebral and intravenous routes. Future studies may show that Mo-Microglia engraftment can occur from the skull BM channels. This study showed a clear transcriptional difference between Mo-Microglia, embryonic microglia, and BAMs, but only focused on the tissue residency period of 6 to 8 weeks.
As per the results, epigenetic priming increases fetal monocytes’ ability to develop into microglia-like cells, which can survive for long periods of time and share transcriptional properties with native microglia. These cells are seen in Alzheimer’s disease brains and correlate with disease severity, suggesting possible pathogenic or compensatory functions. These results may lead to novel treatment techniques for CNS diseases that utilize epigenetically primed monocytes rather than complete hematopoietic stem cell (HSC) transplantation.
Reference: Bastos J, et al. Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1+ microglia. Immunity. 2025. doi:10.1016/j.immuni.2025.04.006
