Review Challenges Classical Monocyte Differentiation and Evaluates Humanized Mouse Models

The classical mononuclear phagocyte system model, which defines a unidirectional trajectory from bone marrow-derived monocytes to terminal tissue macrophages, is undergoing fundamental change. Recent advances in genetic fate mapping and single-cell transcriptomics reveal that most tissue-resident macrophages arise from embryonic precursors and sustain their populations through local self-renewal rather than continuous monocytic recruitment.

In a mini-review published in Cellular & Molecular Biology Letters, researchers synthesize current findings on the hierarchical commitment of murine and human monocytes. The authors highlight evolutionary divergences in phenotypic markers and regulatory checkpoints between the two species, noting that these differences frequently impede clinical translation.

The review examines the transition of circulating monocytes from inflammatory first responders to patrolling vascular guardians. Furthermore, the authors evaluate the molecular mechanisms that regulate how circulating cells extravasate into specialized tissue niches across the body.

Challenging the long-standing terminal differentiation hypothesis, the authors evaluate emerging evidence for myeloid plasticity and recirculation. By analyzing molecular footprinting and the migration of macrophages into lymphatic compartments, the review proposes an updated framework in which these cells function as mobile messengers rather than strictly resident effectors.

To help resolve these paradigms in human immunobiology, the authors evaluate first- and second-generation humanized mouse models, including NSG-derived, cytokine knock-in MI[S]TRG, and cKit-mutant strains. The review details the comparative strengths and limitations of these model systems for investigating human monocyte trafficking and macrophage recirculation.

Subject of Research: Comparative monocyte and macrophage development and humanized mouse models

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

Article References: de Jager, A. L., van der Pan, K., Louis, A., Kassem, S., Naber, B. A. E., de Laat, I. F., Staal, F. J. T., van Dongen, J. J. M., Díez, P., & Teodosio, C. (2026). Comparative development and migratory trajectories of human and murine monocyte–macrophage systems: potential use of next-generation humanized mouse models. Cellular & Molecular Biology Letters. https://doi.org/10.1186/s11658-026-01030-7

Image Credits: AI Generated

DOI: 10.1186/s11658-026-01030-7

Keywords: mononuclear phagocyte system, monocytes, tissue-resident macrophages, humanized mouse models, myeloid plasticity, single-cell transcriptomics, fate mapping, immunobiology, Comparative, development, migratory, trajectories