Donor stem cells home to marrow efficiently and contribute to short- and long-term hematopoiesis after low-cell-dose unconditioned bone marrow transplantation.

Abstract

To study the homing of donor stem cells, their contribution to short- and long-term hematopoiesis, and their functional capacity in an unconditioned marrow transplant model using a clinically relevant low marrow cell dose. A sex-mismatch model was used in which 20 x 10(6) male Balb/cByJ cells were infused into unconditioned female Balb/cByJ mice. Male donor cells were detected in blood and marrow by fluorescence in situ hybridization. Serial transplantation into irradiated secondary recipients was used to assay donor stem cells. Donor hematopoiesis was stimulated after transplant by treating recipients with either stem cell factor (SCF) or sublethal irradiation. Donor-derived male cells were detected in recipient blood (1.2-3.0%) and marrow (2.4-5.4%) for up to 27 weeks, indicating a contribution to short-term hematopoiesis. Male repopulating units approached theoretically expected values, suggesting that transplantation was efficient. Donor stem cell levels after serial transplantation were similar to results observed in primary recipients. Donor stem cell levels 24 hours after infusion (1.3 +/- 0.2% SE) were similar to levels at later time points, indicating that homing was efficient. Stimulation by either SCF or sublethal irradiation after transplant did not alter donor marrow chimerism, suggesting that donor stem cells responded to the stress similarly to endogenous cells. We conclude that in a clinically relevant low-cell-dose unconditioned transplant model, stem cells home to the marrow efficiently, contribute to both short- and long-term hematopoiesis, and, once engrafted, respond to stress effectively. These findings provide a rationale for the use of genetically modified stem cells in clinical protocols that omit intensive conditioning.