We identified two phenotypically, transcriptionally and locally distinct brain macrophages throughout development, giving rise to either microglia or BAMs. We found that two macrophage populations were already present in the yolk sac suggesting an early segregation. Using fate-mapping models, we showed that similar to microglia, BAMs mostly derived from early erythro-myeloid progenitors in the yolk sac. The development of microglia was dependent on the cytokine TGF-β whereas the genesis and maturation of BAMs occurred independently of this cytokine. Collectively, our data show that developing parenchymal and non-parenchymal brain macrophages are separate entities in terms of ontogeny, gene signature and requirement for TGF-β (Utz et al. Cell 2020).
The development of most macrophages depends on the colony-stimulating factor 1 (CSF-1) receptor, which has two ligands: CSF-1 and interleukin-34 (IL-34). While IL-34 is required for the homeostasis of microglia, it is unclear whether BAMs also depend on this cytokine. We demonstrated that the embryonic development of murine BAMs in the choroid plexus, leptomeninges, and perivascular spaces required CSF-1, while IL-34 was critical for their maintenance in adulthood. In the brain, Il34 was expressed by mural cells and perivascular fibroblasts, and its transgenic deletion in these cells interrupted BAM maintenance. Il34 deficiency coincided with transcriptional changes in vascular cells, leading to increased flow velocity and vasomotion in pial and penetrating arterioles. Similarly, Mrc1CreCsf1rfl/fl mice lacking CD206+ perivascular BAMs exhibited increased hemodynamics in arterial networks. These findings reveal a crosstalk between vascular cells and CNS macrophages regulating cerebrovascular function (Van Hove et al. Immunity 2025).
