Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice

Neutrophils are critical mediators during the early stages of innate inflammation in response to bacterial or fungal infections. A human hematopoietic system reconstituted in humanized mice aids in the study of human hematology and immunology. However, the poor development of human neutrophils is a well-known limitation of humanized mice. Here, we generate a human granulocyte colony-stimulating factor (hG-CSF) knockin (KI) NOD/Shi-scid-IL2rgnull (NOG) mouse in which hG-CSF is systemically expressed while the mouse G-CSF receptor is disrupted. These mice generate high numbers of mature human neutrophils, which can be readily mobilized into the periphery, compared with conventional NOG mice. Moreover, these neutrophils exhibit infection-mediated emergency granulopoiesis and are capable of efficient phagocytosis and reactive oxygen species production. Thus, hG-CSF KI mice provide a useful model for studying the development of human neutrophils, emergency granulopoiesis, and a potential therapeutic model for sepsis. [Display omitted] •Neutrophils do not develop in conventional humanized mice transferred with human HSCs•hG-CSF KI mouse shows hyperproduction of hG-CSF with disruption of mG-CSF receptor•Mature human neutrophils can be developed in hG-CSF KI mice after HSC transplantation•E. coli-induced emergency granulopoiesis can be recapitulated in hG-CSF KI mice Ito et al. generate the hG-CSF-expressed NOG mice with target disruption of mG-CSF receptor. Human neutrophils can differentiate in bone marrow and mobilize into peripheral blood of hG-CSF KI mice after human HSC transplantation. These human neutrophils show infection-induced emergency granulopoiesis in the hG-CSF KI mice.