Kit Deficiency Regulates Stable Human Hematopoietic Stem Cell Engraftment in Mice

Humanized mice are required for in-depth analysis of human hematopoietic stem cell (HSC) function and immunobiology. The currently available options are problematic because stable engraftment of substantial numbers of human HSCs and the continuous generation of human myeloid cell types remain difficult to achieve. We generated three novel recipient mouse strains that combine immune deficiency with a functionally impaired endogenous HSC compartment mediated by a defective Kit receptor: BALB/c Rag2- Il2rg-Kit^Wv/Wv (BRgWv), NOD/SCID Il2rg- (NSG) Kit^Wv/Wv (NSGWv) and NSG Kit^W41/W41 (NSGW41). We find that the mutant Kit receptor opens up stem cell niches across species barriers and allows for robust and sustained engraftment of human HSCs after transfer into adult mice without the necessity for irradiation conditioning prior to transplantation. Following stable engraftment in the mouse bone marrow niches, human HSCs give rise to lymphoid cells and to robust numbers of erythroid and myeloid lineage cells over extended periods of time in primary and secondary recipient mice. Particularly in NSGW41 mice, we observe improved reconstitution of human myeloid cell types compared to control irradiated NSG mice. In the bone marrow, endogenous hematopoietic progenitor cells with a defective Kit receptor are largely replaced by human Kit-proficient hematopoietic progenitor cells because progenitor cell expansion requires normal signaling by Kit. Thus, human Kit-proficient donor cells have an advantage over endogenous murine Kit-mutant cells. Increased numbers of myeloid cells are found in the bone marrow and spleen of NSGW41 transplanted mice compared with grafts established in irradiated NSG mice. We conclude that Kit-signaling regulates HSC engraftment across the human-mouse species barrier and that Kit deficient mice show great potential for the study of human HSC functions including self-renewal, differentiation and mechanisms of innate immunity.