Adult hematopoietic stem cells lacking Hif-1α self-renew normally

The hematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow microenvironment. Cellular responses to hypoxia are largely mediated by the hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated a subunits of Hif-1 and Hif-2 (namely, Hif-1 alpha and Hif-2 alpha) form dimers with their stably expressed beta subunits and control the transcription of downstreamhypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1 alpha is essential for HSC maintenance, whereby Hif-1 alpha-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2 alpha is dispensable for cell-autonomous HSC maintenance, both under steady-state conditions and following transplantation. Given these unexpected findings, we set out to revisit the role of Hif-1 alpha in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1 alpha has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1 alpha efficiently self-renew and sustain long-term multilineage hematopoiesis upon serial transplantation. Finally, Hif-1 alpha-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the bone marrow microenvironment, Hif-1 alpha is dispensable for cell-autonomous HSC maintenance.