Conserved phenotype and function of human brain border-associated macrophages in iPSC-derived models

Border-associated macrophages (BAMs) are increasingly implicated in protective brain functions including the removal of pathogenic material such as amyloid-beta (Aβ). However, there is a lack of available and deeply characterized human BAM models. Here, we report that postnatal transplantation of induced pluripotent stem (iPS) cell-derived hematopoietic progenitors to the murine brain sufficiently chimerizes the brain border immune compartment to allow functional interrogations. Human xenotransplanted BAMs (xBAMs) line the leptomeninges and brain vasculature beyond the glia limitans. Via single-cell RNA sequencing, we show that a conserved transcriptional signature distinguishes BAMs from microglia across species origin, age, and genetic background. Both xBAMs and murine BAMs are defined by a hyper-endocytic phenotype and function, surpass other brain macrophages in acute Aβ scavenging, and exhibit compartment-restricted sampling of parenchymal material. Using a modified differentiation protocol, we find that we can generate iPS-derived BAM-like cells (iBAMs) <i>in vitro</i>, which are also characterized by a hyper-endocytic phenotype and enhanced engulfment capacity relative to iPS-derived microglia-like cells (iMGLs). Together, these data define a conserved hyper-endocytic BAM phenotype and provide a toolbox for studying human BAMs both <i>in vivo</i> and <i>in vitro</i>.