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It has been proposed that bone marrow (BM) hematopoietic stem and progenitor cells are distributed along an oxygen (O 2) gradient, where stem cells reside in the most hypoxic areas and proliferating progenitors are found in O 2-rich areas. However, the effects of hypoxia on human hematopoietic stem cells (HSCs) have not been characterized. Our objective was to evaluate the functional and molecular responses of human BM progenitors and stem cells to hypoxic conditions. BM lineage–negative (Lin–) CD34+ CD38–cells were cultured in serum-free medium under 1.5% O 2 (hypoxia) or 20% O 2 (normoxia) for 4 days. Using limiting dilution analysis, we demonstrate that the absolute number of SCID-repopulating cells (SRCs) increased by 5.8-fold in hypoxic cultures compared with normoxia, and by 4.2-fold compared with freshly isolated Lin–CD34+ CD38–cells. The observed increase in BM-repopulating …