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

Milica Vukovic, Catarina Sepulveda, Chithra Subramani, Amelie Guitart, J. Mohr, Lewis Allen, Theano I Panagopoulou, Jasmin Paris, Hannah Lawson, Arnaud Villacreces, Alejandro Armesilla-Diaz, Deniz Gezer, Tessa Holyoake, Peter J Ratcliffe, Kamil Kranc

Research output: Contribution to journalArticlepeer-review

Abstract

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 α subunits of Hif-1 and Hif-2 (namely, Hif-1α and Hif-2α) form dimers with their stably expressed β subunits and control the transcription of downstream hypoxia-responsive genes to facilitate adaptation to low oxygen tension. An initial study concluded that Hif-1α is essential for HSC maintenance, whereby Hif-1α–deficient HSCs lost their ability to self-renew in serial transplantation assays. In another study, we demonstrated that Hif-2α 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-1α in cell-autonomous HSC functions. Here we demonstrate that inducible acute deletion of Hif-1α has no impact on HSC survival. Notably, unstressed HSCs lacking Hif-1α efficiently self-renew and sustain long-term multilineage hematopoiesis 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 bone marrow microenvironment, Hif-1α is dispensable for cell-autonomous HSC maintenance.
Original languageEnglish
Pages (from-to)2841-2846
JournalBlood
Volume127
Issue number23
Early online date8 Apr 2016
DOIs
Publication statusE-pub ahead of print - 8 Apr 2016

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