Bastos J, O'Brien C, Vara-Pérez M, Mampay M, van Olst L, Barry-Carroll L, Kancheva D, Leduc S, Lievens AL, Ali L, Vlasov V, Meysman L, Shakeri H, Roelandt R, Van Hove H, De Vlaminck K, Scheyltjens I, Yaqoob F, Lombroso SI, Breugelmans M, Faron G, Gomez-Nicola D, Gate D, Bennett FC, Movahedi K. Monocytes can efficiently replace all brain macrophages and fetal liver monocytes can generate bona fide SALL1+ microglia. Immunity. 2025 May 13;58(5):1269-1288.e12. Epub 2025 Apr 30 PubMed.
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Weill College Medicine, New York
This interesting paper, together with Aisenberg et al., 2025, demonstrates that brain-resident myeloid cells, including microglia and border-associated macrophages, can be replaced by circulating monocytes. Such replacement can be clinically beneficial in a mouse model of Krabbe disease in which microglia seem to play a pathogenic role. These findings shed light on a poorly understood aspect of the ontogeny, homeostasis, and renewal of distinct classes of brain-resident myeloid cells, and provide the foundation for further studies exploring the therapeutic opportunities afforded by these new developments.
It was already known that bone marrow-derived macrophages do not fully replicate the transcriptome of yolk sac-derived microglia, but the reason was unknown. Bastos et al discovered that it may have to do with the lack of chromatin accessibility to Sall1. However, fetal liver macrophages, once in brain, show increased chromatin accessibility to the Sall1 locus, more fully recapitulating the transcriptional profile of yolk sac microglia. Whether these liver-derived macrophages fully phenocopy the functional properties of native microglia remains to be determined. Another promising finding emerged from Aisenberg et al.’s studies in the Krabbe disease mouse model. Microglia replacement alone—without the need for bone marrow transplantation or myeloablation—was sufficient to improve survival, ameliorate white-matter pathology, and reduce clinical deficits. These findings hold significant translational potential.
This is a major step forward in brain resident myeloid cell biology and pathobiology. Needless to say the work needs to be validated in humans.
The finding that cells with the molecular signature of monocyte-derived microglia are present in the brain of AD patients is extremely important since it raises the possibility of using circulating monocytes as carriers of pharmacological agents (small molecules, biologics, etc.) that may have hard time crossing the BBB, even in conditions like AD in which the BBB may be more permeable. Furthermore, microglial replacement could be used as a therapeutic approach in AD in which microglial dysfunction has been implicated. A caveat is that, in AD, microglia may be beneficial or detrimental depending on the stage of disease, which would require establishing the time window in which such replacement is likely to be beneficial.
References:
Aisenberg WH, O'Brien CA, Sangster M, Yaqoob F, Zhang Y, Temsamrit B, Thom S, Gosse L, Chaluvadi S, Elfayomi B, Lee G, Polam V, Levitt EM, Liu G, Lombroso SI, Nemec KM, Clowry G, Nieves C, Rawat P, Church E, Martinez D, Shoffler C, Kancheva D, Petucci C, Taylor D, Kofler J, Erskine D, Movahedi K, Bennett ML, Bennett FC. Direct microglia replacement reveals pathologic and therapeutic contributions of brain macrophages to a monogenic neurological disease. Immunity. 2025 May 13;58(5):1254-1268.e9. Epub 2025 Apr 30 PubMed.
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