Humanization of CD47 enables development of functional human neutrophils via post-irradiation remodeling of the bone marrow.

A major limitation of current models is suboptimal myelopoiesis, particularly lack of functional human neutrophils, hampering the modeling of human immune responses and chronic diseases. Here, we describe a novel humanized mouse model, named MaGIC for genes replaced, in the C57Bl/6N strain, which improves human myelopoiesis and enables development of functional human neutrophils. In MaGIC mice, human cytokines M-CSF/CSF1(M), GM-CSF/CSF2(G) and IL-6(I) are knocked-in replacing mouse genes and murine IL2rg and Rag1(a) are deleted. Human THPO in these mice supports human hematopoiesis. More importantly, insertion of human CD47 (C) under the control of endogenous mouse CD47 promoter enables xenotransplantation and human neutrophil development. We characterized the transcriptome of human neutrophils from MaGIC mice using 10x Genomics. MaGIC mice support all human neutrophil subsets found in human bone marrow and blood, a major improvement. Overall design: Blood, bone marrow, and spleen from MaGIC mice were hashed and sequenced using 10x single cell 3' v3.1 RNA-sequencing.