Abstract
BackgroundHumanized mice (hu mice) are based on the transplantation of hematopoietic stem and progenitor cells into immunodeficient mice and have become important pre-clinical models for biomedical research. However, data about their hematopoiesis over time are scarce. We therefore characterized leukocyte reconstitution in NSG mice, which were sublethally irradiated and transplanted with human cord blood-derived CD34+ cells at newborn age, longitudinally in peripheral blood and, for more detailed analyses, cross-sectionally in peripheral blood, spleen and bone marrow at different time points.ResultsHuman cell chimerism and absolute human cell count decreased between week 16 and 24 in the peripheral blood of hu mice, but were stable thereafter as assessed up to 32 weeks. Human cell chimerism in spleen and bone marrow was maintained over time. Notably, human cell chimerism in peripheral blood and spleen as well as bone marrow positively correlated with each other. Percentage of B cells decreased between week 16 and 24, whereas percentage of T cells increased; subsequently, they levelled off with T cells clearly predominating at week 32. Natural killer cells, monocytes and plasmacytoid dendritic cells (DCs) as well as CD1c + and CD141+ myeloid DCs were all present in hu mice. Proliferative responses of splenic T cells to stimulation were preserved over time. Importantly, the percentage of more primitive hematopoietic stem cells (HSCs) in bone marrow was maintained over time.ConclusionsOverall, leukocyte reconstitution was maintained up to 32 weeks post-transplantation in our hu NSG model, possibly explained by the maintenance of HSCs in the bone marrow. Notably, we observed great variation in multi-lineage hematopoietic reconstitution in hu mice that needs to be taken into account for the experimental design with hu mice.
Highlights
Humanized mice are based on the transplantation of hematopoietic stem and progenitor cells into immunodeficient mice and have become important pre-clinical models for biomedical research
The aim here was to assess whether leukocyte reconstitution in hu NSG mice is maintained beyond week 24 post-transplantation. We addressed this question by monitoring human cell chimerism, absolute human cell count and reconstitution of B and T cells longitudinally between week 16 and 32 in peripheral blood
Absolute human cell count and reconstitution of B and T cells in peripheral blood As most studies using hu mice are performed between week 12 and 24 weeks post-transplantation, we first monitored human cell chimerism and reconstitution of B and T cells in peripheral blood longitudinally every four weeks between week 12 and 24 after transplantation with cord blood-derived CD34+ cells in two groups of hu mice
Summary
Humanized mice (hu mice) are based on the transplantation of hematopoietic stem and progenitor cells into immunodeficient mice and have become important pre-clinical models for biomedical research. Data about their hematopoiesis over time are scarce. Humanized mice (hu mice) generated via the transplantation of human hematopoietic stem and progenitor cells (HSPCs), fetal tissues or mature immune cells into immunodeficient mice serve as small animal models for biomedical research [1]. Various immunodeficient mouse strains are in use for the generation of hu mice. The mouse SIRPα allele on macrophages of Non-obesediabetic (NOD) mice efficiently recognizes the human CD47 on engrafted cells and prevents their. The SIRPα allele of C57BL/6 mice does not bind to human CD47 and does not trigger this inhibitory axis, resulting in phagocytosis of xenotransplanted cells and lack of reconstitution of human hematopoiesis; the SIRPα allele of BALB/c mice moderately binds to human CD47, resulting in limited graft efficiency [7]
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