Abstract
Donor-matched transplantation of hematopoietic stem cells (HSCs) is widely used to treat hematologic malignancies but is associated with high mortality. The expansion of HSC numbers and their mobilization into the bloodstream could significantly improve therapy. We report here that adult mice conditionally deficient for the transcription Growth factor independence 1b (Gfi1b) show a significant expansion of functional HSCs in the bone marrow and blood. Despite this expansion, Gfi1bko/ko HSCs retain their ability to self-renew and to initiate multilineage differentiation but are no longer quiescent and contain elevated levels of reactive oxygen species. Treatment of Gfi1bko/ko mice with N-acetyl-cystein significantly reduced HSC numbers indicating that increased reactive oxygen species levels are at least partially responsible for the expansion of Gfi1b-deficient HSCs. Moreover, Gfi1b−/− HSCs show decreased expression of CXCR4 and Vascular cell adhesion protein-1, which are required to retain dormant HSCs in the endosteal niche, suggesting that Gfi1b regulates HSC dormancy and pool size without affecting their function. Finally, the additional deletion of the related Gfi1 gene in Gfi1bko/ko HSCs is incompatible with the maintenance of HSCs, suggesting that Gfi1b and Gfi1 have partially overlapping functions but that at least one Gfi gene is essential for the generation of HSCs.
Reactive oxygen species contribute to dysfunction of bone marrow hematopoietic stem cells in aged C57BL/6 J mice
