B9: Formation of a human hematopoietic stem cell niche in the murine bone marrow

Project leader: Dr. C. Waskow

Complex biological processes like hematopoiesis require in vivo analysis, but the study of human hematopoietic stem cell (HSC) biology in vivo is severely limited by ethical and technical constraints. The establishment of human hematopoiesis in mice would allow the analysis of ‘human’ HSC biology, and the establishment of a functional ‘human’ immune system in mice would make the study of immune responses, including autoimmunity, infectious diseases, cancer biology and regenerative medicine, feasible in vivo. Stable and sustained engraftment of human HSCs in mice is essential for the continuous generation of human blood cells after transplantation. However, to date, most xeno-transplantations of human HSCs into genetically modified recipient mice result in the transient generation of immune cells, but it has been proven difficult to obtain long-term engraftment of human HSCs, suggesting that self-renewal and maintenance of human HSC is impaired. Therefore, we plan to create a murine HSC niche accessible to human HSCs, allowing for stable and sustained engraftment. We recently defined all parameters necessary and sufficient to support complete and sustained HSC replacement by histoincompatible (allogeneic) donor cells in mice, and we now plan to test the hypothesis that genetic ‘weakening’ of endogenous mouse HSCs, combined with immuno-deficiency and strain-background-specific modifiers, facilitates the efficient generation of a human HSC niche in mice.