ERα promotes murine hematopoietic regeneration through the Ire1α-mediated unfolded protein response

Elife. 2018 Feb 16:7:e31159. doi: 10.7554/eLife.31159.


Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration.

Keywords: Hematopoietic stem cells; Ire1; developmental biology; estrogen; irradiation; mouse; regeneration; stem cells; unfolded protein response.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cells, Cultured
  • Endoribonucleases / metabolism*
  • Estrogen Receptor alpha / metabolism*
  • Estrogens / metabolism*
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / physiology*
  • Mice
  • Protein Serine-Threonine Kinases / metabolism*
  • Signal Transduction
  • Unfolded Protein Response*


  • Estrogen Receptor alpha
  • Estrogens
  • Ern1 protein, mouse
  • Protein Serine-Threonine Kinases
  • Endoribonucleases