Vukovic, M. et al. (2016) Adult haematopoietic stem cells lacking Hif-1α self-renew normally. Blood, 127(23), pp. 2841-2846. (doi: 10.1182/blood-2015-10-677138) (PMID:27060169) (PMCID:PMC4956613)
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Abstract
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 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 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-1α is dispensable for cell-autonomous HSC maintenance.
| Item Type: | Articles |
|---|---|
| Status: | Published |
| Refereed: | Yes |
| Glasgow Author(s) Enlighten ID: | Gezer, Dr Deniz and Holyoake, Professor Tessa |
| Authors: | Vukovic, M., Sepulveda, C., Subramani, C., Guitart, A. V., Mohr, J., Allen, L., Panagopoulou, T. I., Paris, J., Lawson, H., Villacreces, A., Armesilla-Diaz, A., Gezer, D., Holyoake, T. L., Ratcliffe, P. J., and Kranc, K. R. |
| College/School: | College of Medical Veterinary and Life Sciences > School of Cancer Sciences |
| Journal Name: | Blood |
| Publisher: | American Society of Hematology |
| ISSN: | 0006-4971 |
| ISSN (Online): | 1528-0020 |
| Published Online: | 08 April 2016 |
| Copyright Holders: | Copyright © 2016 American Society of Hematology |
| First Published: | First published in Blood 127(23):2841-2846 |
| Publisher Policy: | Reproduced in accordance with the copyright policy of the publisher |
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