Abstract
SummaryHematopoietic stem cells (HSCs) are typically characterized by transplantation into irradiated hosts in a highly perturbed microenvironment. Here, we show that selective and temporally controlled depletion of resident HSCs through genetic deletion of Gata2 constitutes efficient recipient conditioning for transplantation without irradiation. Strikingly, we achieved robust engraftment of donor HSCs even when delaying Gata2 deletion until 4 weeks after transplantation, allowing homing and early localization to occur in a completely non-perturbed environment. When HSCs from the congenic strains Ly5.1 and Ly5.2 were competitively transplanted, we found that the more proliferative state of Ly5.2 HSCs was associated with superior long-term engraftment when using conditioning by standard irradiation, while higher CXCR4 expression and a better homing ability of Ly5.1 HSCs strongly favored the outcome in our inducible HSC depletion model. Thus, the mode and timing of recipient conditioning challenges distinct functional features of transplanted HSCs.
Highlights
The functionality of hematopoietic stem cells (HSCs) can be characterized in vivo by transplantation into recipients that lack a functional hematopoietic system (Till and Mc, 1961)
It is a general notion in the field that the engraftment of donor HSCs is dependent on the availability of niches that normally are occupied by host HSCs (Bhattacharya et al, 2006, 2009; Schofield, 1978; Tomita et al, 1994)
One week after the last poly(IC) injection, the mice started to succumb (Figure 1C) and prior to this we observed a decrease of platelet and white blood cell counts in the peripheral blood (PB) (Figure 1D)
Summary
The functionality of hematopoietic stem cells (HSCs) can be characterized in vivo by transplantation into recipients that lack a functional hematopoietic system (Till and Mc, 1961). Self-renewal and multi-lineage reconstitution capacity can be assessed in transplantation assays, and are the key criteria to define HSCs (Kiel et al, 2005; Osawa et al, 1996; Smith et al, 1991). It is a general notion in the field that the engraftment of donor HSCs is dependent on the availability of niches that normally are occupied by host HSCs (Bhattacharya et al, 2006, 2009; Schofield, 1978; Tomita et al, 1994). It is unclear to what degree the functional properties of HSCs assessed in an environment perturbed by irradiation reflect those seen during steady-state hematopoiesis or more physiological challenges (Busch et al, 2015; Busch and Rodewald, 2016; Sun et al, 2014)
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