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

نویسندگان

  • Milica Vukovic
  • Catarina Sepulveda
  • Chithra Subramani
  • Amélie V Guitart
  • Jasmine Mohr
  • Lewis Allen
  • Theano I Panagopoulou
  • Jasmin Paris
  • Hannah Lawson
  • Arnaud Villacreces
  • Alejandro Armesilla-Diaz
  • Deniz Gezer
  • Tessa L Holyoake
  • Peter J Ratcliffe
  • Kamil R Kranc
چکیده

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.

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عنوان ژورنال:
  • Blood

دوره 127 23  شماره 

صفحات  -

تاریخ انتشار 2016