Adult haematopoietic stem cells lacking Hif-1α self-renew normally.
Vukovic M., Sepulveda C., Subramani C., Guitart AV., Mohr J., Allen L., Panagopoulou TI., Paris J., Lawson H., Villacreces A., Armesilla-Diaz A., Gezer D., Holyoake TL., Ratcliffe PJ., Kranc KR.
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.