25 okt. 2025
Du et al. (BioRxiv) DOI: 10.1101/2024.08.08.606900
Keywords
Yolk-sac derived microglia
Monocyte-derived macrophages
Cell origin
Brain immunology
Main Findings
Microglia are the primary resident myeloid cell in the brain and the primary immune cell type found in the central nervous system (CNS) [1]. Through constant environment sampling and surveillance, they support neuronal health and blood brain barrier (BBB) integrity [2–4]. Their complex morphology, high phagocytic ability and process motility enable them to quickly respond to insults and neuroinflammation within the brain, by clearing pathogens or debris, releasing pro- or anti- inflammatory cytokines, such as TNF-α or Interleukin 10 respectively, initiating the immune cell recruitment and immune response or dampening excessive inflammation [5–7]. However, chronically activated microglia can contribute to neuropathology and neurodegeneration. For example, in Alzheimer Disease, microglia cluster around amyloid β and attempt to clear plaques [8]; in Parkinson Disease microglia release neurotoxic factors contributing to neuronal death [9], and in Multiple Sclerosis they contribute to demyelination and axonal damage [10]. Replacement of these disease-associated, dysfunctional microglia with health homeostatic microglia could be an effective strategy to ameliorate disease, and motivates the search for the true origin of homeostatic versus disease-associated microglia in the adult brain.
Microglia, similarly to tissue resident macrophages, originate from yolk sac progenitor cells and colonize brain early in the development before the formation of the BBB [11,12]. Although microglia are fully differentiated cells, they retain the capacity for self-renew and repopulate brain parenchyma, with seemingly little contribution from circulating monocytes [13]. Pharmacological microglia ablation studies demonstrated that following treatment withdrawal, functional microglia repopulate the brain parenchyma at normal density [14]. The origin of these repopulated microglia cells remains poorly understood, which makes developing targeted replacement therapies challenging.
To address this question, in their preprint (not peer reviewed) Du et al compared yolk sac (YS) derived microglia with monocyte derived macrophages (MDM) that engrafted the brain parenchyma in homeostatic conditions, but after prolonged microglia depletion. To do so, the authors utilized genetic mouse models to selectively label and track cells derived from monocytes. They depleted endogenous microglia by placing mice on PLX5622 diet, a commonly used approach for pharmacological microglia depletion, and searched for the presence of cells derived from these two cell populations. The authors find that in the normal brain, MDM are present in only small quantities and in only a few brain regions. However, following prolonged microglial depletion, MDM repopulate the entire brain in significant number. Importantly, engrafted MDM acquire a morphology distinctly different from YS derived microglia and more reminiscent of activated microglia. Moreover, the engrafted cells show a as well as a unique transcriptional signature marked by upregulation of genes involved in cell adhesion, pathogen recognition and phagocytosis. Comparison to publicly available datasets suggested that MDM are more similar to peripherally derived macrophages or bone marrow derived cell rather than homeostatic YS derived microglia. Furthermore, transient expression of markers such as CD206 combined with epigenetic profiling analysis suggested that during the brain engraftment process MDM undergo tissue imprinting in the meningeal spaces. Lastly, to understand the anatomic sources of MDM, the authors performed a series of experiments utilizing either parabiotic mice or skull transplants that collectively show that both blood derived and skull derived monocytes are capable of engraftment within brain parenchyma and replenishment of microglia.
Limitations
Du and colleagues set out to address one of the central questions in the field of neuroimmunology: what is the origin and the identity of microglia within the adult brain parenchyma. Through rigorous and innovative experiments, the authors demonstrate that monocytes from two different sources can repopulate microglia after depletion of endogenous microglia, yet repopulated cells display a unique transcriptional profile, most comparable to MDMs. This unexpected finding significantly advances our understanding of microglia ontogeny and heterogeneity, and may guide the future development of therapeutic strategies aimed at replacing disease associated microglia with newly engrafted homeostatic microglia. While the study offers important and compelling insights, a few questions remain:
While the authors convincingly demonstrate the ability of blood and skull derived cells to engraft within brain parenchyma, and that engrafted cells show a unique morphology, it remains to be shown whether these MDM cells can functionally replace YS-derived microglia in their homeostatic roles. It is also unclear whether engrafted cells persist long-term within the brain parenchyma.
Given that MDM have upregulated genes involved in phagocytosis or pathogen recognition, it should be tested whether these cells are more adapt to respond to neuroinflammation or neurodegeneration. This could provide critical insights into their potential as a viable therapeutic strategy.
Although the authors have demonstrated that the absence of microglia can trigger MDM engraftment, it would be important to identify molecular cues that are guiding those cells to engraft within brain.
Significance/Novelty
Du at al provide compelling evidence that in the absence of microglia, both circulating monocytes and skull derived cells can repopulate brain parenchyma and adopt a distinct transcriptional profile. There findings add a new layer of complexity to our understanding of microglia ontogeny. By focusing on cellular origin and molecular profiling in homeostatic conditions, the authors challenge the long-standing paradigm of yolk sac–derived microglial exclusivity and highlight more adaptable system than previously appreciated. While the functional capacity of these engrafted cells remains to be fully elucidated, their potential therapeutic utility in neuroinflammatory and neurodegenerative contexts is an exciting avenue for future investigation.
Credit
Reviewed by Katarzyna Stasiak and Harald Sontheimer as part of a cross-institutional journal club between the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the University of Virginia, the Medical University of Vienna and other life science institutes in Vienna.
The author declares no conflict of interests in relation to their involvement in the review.
References
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