Hif-2α is not essential for cell-autonomous hematopoietic stem cell maintenance

Local hypoxia in hematopoietic stem cell (HSC) niches is thought to regulate HSC functions. Hypoxia-inducible factor-1 (Hif-1) and Hif-2 are key mediators of cellular responses to hypoxia. Although oxygen-regulated alpha-subunits of Hifs, namely Hif-1 alpha and Hif-2 alpha, are closely related, they play overlapping and also distinct functions in nonhematopoietic tissues. Although Hif-1 alpha-deficient HSCs lose their activity on serial transplantation, the role for Hif-2 alpha in cell-autonomous HSC maintenance remains unknown. Here, we demonstrate that constitutive or inducible hematopoiesis-specific Hif-2 alpha deletion does not affect HSC numbers and steady-state hematopoiesis. Furthermore, using serial transplantations and 5-fluorouracil treatment, we demonstrate that HSCs do not require Hif-2 alpha to self-renew and recover after hematopoietic injury. Finally, we show that Hif-1 alpha deletion has no major impact on steady-state maintenance of Hif-2 alpha-deficient HSCs and their ability to repopulate primary recipients, indicating that Hif-1 alpha expression does not account for normal behavior of Hif-2 alpha-deficient HSCs.