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

Abstract

Summary 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 the central nervous system controls embryonic HSPC production 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, while 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 production 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.

The First Fifteen Years of Steroid Receptor Research in Zebrafish; Characterization and Functional Analysis of the Receptors

“…Administration of the antidepressant fluoxetine as well as social interactions were shown to restore normal behavior [75,77]. Using this mutant, it was demonstrated that Gr mediates the glucocorticoid-induced inhibition of leukocyte migration upon wounding [78] and the stimulation of the formation of hematopoietic stem and progenitor cells (HSPCs) by glucocorticoids [79]. In addition, it was found that light adaptation in the retina was disturbed in mutant larvae [80].…”

Outside the brain: an inside view on transgenic animal and stem cell-based models to examine neuronal serotonin-dependent regulation of HPA axis-controlled events during development and adult stages

“…Just as neurons process stimuli coming from outside the CNS, neuronal activity also initiates, controls or regulates events occurring outside the CNS. North and colleagues investigated central regulatory mechanisms in hematopoietic stem (HPS) cell production during the embryonic development of zebrafish (22). Generally, the formation and maintenance of HPS cells are characterized by precisely tuned mechanisms that bring together various cellular signals and result in a balance of HPS cell selfrenewal and differentiation.…”

Stress Can Be a Good Thing for Blood Formation

“…However, some signals travel long distances through the circulation to regulate blood cell formation. In this issue, Kwan et al (Kwan et al, 2016) report that a pathway activated by stress in the brain promotes hematopoietic stem and progenitor cell (HSPC) formation at a distance in the dorsal aorta of zebrafish embryos.…”

“…In this issue, Kwan et al (Kwan et al, 2016) determine the mechanism by which one of these regulators, serotonin, enhances HSPC formation. Serotonin is a monoamine derived from tryptophan.…”

“…TPH1 produces serotonin in the periphery, while TPH2 controls serotonin production by serotonergic neurons in the brain. To determine which source of serotonin is most important for HSPC formation, Kwan et al (Kwan et al, 2016) performed morphilino knockdowns of the TPH1 ( tph1a , tph1b ) and TPH2 ( tph2 ) genes. All knockdowns decreased blood cell production in the dorsal aorta.…”