Comparative development and migratory trajectories of human and murine monocyte–macrophage systems: potential use of next-generation humanized mouse models

The classical mononuclear phagocyte system (MPS) model, defining a unidirectional trajectory from bone marrow-derived monocytes to terminal tissue macrophages, is currently undergoing fundamental change. Recent advances in genetic fate mapping and single-cell transcriptomics have revealed a complex landscape where most tissue-resident macrophages (TRMs) arise from embryonic precursors and maintain themselves through local self-renewal, rather than continuous monocytic recruitment. In this review, we integrate current knowledge on hierarchical commitment of murine and human monocytes, emphasizing evolutionary differences in phenotypic markers and regulatory checkpoints that often hamper clinical translation. We examine the transition of circulating monocytes, from inflammatory “first responders” to patrolling vascular guardians, and evaluate the molecular mechanisms regulating their extravasation into specialized tissue niches. Crucially, we challenge the long-standing “terminal differentiation” hypothesis by evaluating emerging evidence for myeloid plasticity and recirculation. By discussing molecular footprinting and the migration of macrophages to lymphatic compartments, we propose a model in which these cells act as mobile messengers rather than resident effectors. Finally, we provide an in-depth assessment of first- and second-generation humanized mouse models, including NSG-derived, cytokine knock-in (MI[S]TRG), and cKit-mutant strains, as an essential bridge for resolving these paradigms in human immunobiology, describing their comparative strengths and limitations for studying human monocyte trafficking and macrophage recirculation.