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

Area of Science:

• Neuroimmunology
• Stem Cell Biology
• Macrophage Biology

Background:

• Border-associated macrophages (BAMs) play vital roles in brain immunity, including clearing amyloid-beta (Aβ).
• Existing human BAM models are limited, hindering comprehensive study.
• Understanding BAM function is critical for neurodegenerative disease research.

Purpose of the Study:

• To develop and characterize human BAM models for functional studies.
• To investigate the conserved transcriptional and functional properties of BAMs across species.
• To establish in vitro and in vivo tools for studying human BAMs.

Main Methods:

• Postnatal transplantation of human induced pluripotent stem (iPS) cell-derived hematopoietic progenitors into murine brains.
• Single-cell RNA sequencing to analyze transcriptional signatures of xenotransplanted BAMs (xBAMs) and murine BAMs.
• In vitro differentiation of iPS cells to generate BAM-like cells (iBAMs) and microglia-like cells (iMGLs).

Main Results:

• Human iPS cell-derived progenitors successfully engrafted and differentiated into xBAMs, populating brain borders.
• A conserved hyper-endocytic phenotype and enhanced Aβ scavenging capacity were identified in both xBAMs and murine BAMs.
• In vitro iBAMs exhibited superior phagocytic capabilities compared to iMGLs.
• Compartment-restricted sampling of parenchymal material by BAMs was observed.

Conclusions:

• A conserved hyper-endocytic phenotype defines BAMs across species, highlighting their specialized function in brain immune surveillance.
• The study provides novel in vivo and in vitro models for investigating human BAMs.
• These models offer valuable tools for understanding BAM roles in neurological health and disease, particularly in Aβ clearance.