The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling

Cell Stem Cell. 2016 Sep 1;19(3):370-82. doi: 10.1016/j.stem.2016.06.004. Epub 2016 Jul 14.


Hematopoietic stem and progenitor cell (HSPC) specification is regulated by numerous defined factors acting locally within the hemogenic niche; however, it is unclear whether production can adapt to fluctuating systemic needs. Here we show that the CNS controls embryonic HSPC numbers via the hypothalamic-pituitary-adrenal/interrenal (HPA/I) stress response axis. Exposure to serotonin or the reuptake inhibitor fluoxetine increased runx1 expression and Flk1(+)/cMyb(+) HSPCs independent of peripheral innervation. Inhibition of neuronal, but not peripheral, tryptophan hydroxlyase (Tph) persistently reduced HSPC number. Consistent with central HPA/I axis induction and glucocorticoid receptor (GR) activation, GR agonists enhanced, whereas GR loss diminished, HSPC formation. Significantly, developmental hypoxia, as indicated by Hif1α function, induced the HPA/I axis and cortisol production. Furthermore, Hif1α-stimulated HSPC enhancement was attenuated by neuronal tph or GR loss. Our data establish that embryonic HSC production responds to physiologic stress via CNS-derived serotonin synthesis and central feedback regulation to control HSC numbers.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Count
  • Cell Hypoxia / drug effects
  • Cell Proliferation / drug effects
  • Central Nervous System / metabolism*
  • Embryo, Nonmammalian / drug effects
  • Embryo, Nonmammalian / metabolism
  • Embryonic Stem Cells / drug effects
  • Embryonic Stem Cells / metabolism*
  • Fluoxetine / pharmacology
  • Hematopoietic Stem Cells / drug effects
  • Hematopoietic Stem Cells / metabolism*
  • Hypothalamo-Hypophyseal System / drug effects
  • Hypothalamo-Hypophyseal System / metabolism
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism
  • Kidney / drug effects
  • Kidney / metabolism
  • Receptors, Glucocorticoid / metabolism*
  • Serotonergic Neurons / drug effects
  • Serotonergic Neurons / metabolism
  • Serotonin / pharmacology
  • Signal Transduction* / drug effects
  • Stress, Physiological / drug effects
  • Sympathetic Nervous System / drug effects
  • Sympathetic Nervous System / metabolism
  • Tryptophan Hydroxylase / metabolism
  • Zebrafish / embryology


  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Receptors, Glucocorticoid
  • Fluoxetine
  • Serotonin
  • Tryptophan Hydroxylase