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The haematopoietic stem cell (HSC) pool is maintained under hypoxic conditions within the bone marrow (BM) microenvironment. Cellular responses to hypoxia are largely mediated by hypoxia-inducible factors, Hif-1 and Hif-2. The oxygen-regulated alpha subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed beta subunits, and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded thatHif-1αis essential for HSC maintenance, wherebyHif-1α-deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated thatHif-2αis 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 ofHif-1αin cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion ofHif-1αhas no impact on HSC survival. Notably, unstressed HSCs lackingHif-1αefficiently self-renew and sustain long-term multilineage haematopoiesis upon serial transplantation. Finally,Hif-1α-deficient HSCs recover normally after hematopoietic injury induced by serial administration of 5-fluorouracil. We therefore conclude that despite the hypoxic nature of the BM microenvironment,Hif-1αis dispensable for cell-autonomous HSC maintenance.


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MRC Centre for Regenerative Medicine, University of Edinburgh, Edinburgh, United Kingdom;