LAUSR

Hematopoietic stem cells (HSCs) are defined as the cells that have the ability of both multi-potency and self-renewal. This property of HSCs has traditionally been characterized by transplantation assays where the donor HSCs are transferred into the animal where the hematopoietic system has been ablated. In this assay, long-term sustained and multi-lineage reconstitution are the criteria to define the functional HSCs. However, recent technical advances that allow the monitoring of HSC kinetics in steady-state animals, have led to the discovery that steady-state hematopoiesis differs qualitatively from that assessed in the transplantation assay. In the ablated (irradiated) recipients, HSCs are forced to proliferate in order to sustain the hematopoietic system, while steady-state hematopoiesis is rather maintained by proliferating progenitors. It still remains unclear to what degree post-transplantation hematopoiesis reflects normal HSC physiology. To explore the HSC dynamics under different transplantation conditioning regimens, we developed the Mx1Cre-Gata2 mouse model where endogenous HSCs can be selectively depleted following inducible removal of Gata2 as a crucial factor for HSCs. In this manner the rest of the hematopoietic system and the microenvironment remains intact, and transplanted HSCs can still engraft efficiently. We found that the kinetics of transplanted HSCs are quite different compared to standard conditioning by irradiation, and that different properties of the HSCs are challenged in the two models. In our selective HSC depletion model, properties influencing homing and lodgement in the bone marrow influence the engraftment capacity to a greater extent, while proliferative capacity of the HSCs is more stringently assessed in the irradiation model. Thus, distinct aspects of fitness and function are measured when transplanted HSCs are challenged in different environments.