Efficient differentiation of human neutrophils with recapitulation of emergency granulopoiesis in human G-CSF knockin humanized mice
Ryoji Ito, Ikumi Katano, Immanuel Kwok, Lai Guan Ng, Miyuki Ida-Tanaka, Yusuke Ohno, Yunmei Mu, Hanako Morita, Eiko Nishinaka, Chiyoko Nishime, Misa Mochizuki, Kenji Kawai, Tay Hui Chien, Zhao Yunqian, Yiping Fan, Liew Hui Hua, Teja Celhar, Jerry Kok Yen Chan, Takeshi Takahashi, Motohito Goto, Tomoyuki Ogura, Riichi Takahashi, Mamoru Ito
Abstract
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 -IL2rg null (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.