Kwan W, Cortes M, Frost I, Esain V, Theodore LN, Liu SY, Budrow N, Goessling W, North TE. The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling. Cell Stem Cell. 2016 09 01; 19(3):370-82.

Citation

Kwan W, Cortes M, Frost I, Esain V, Theodore LN, Liu SY, Budrow N, Goessling W, North TE. 2016. The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling. Cell stem cell. 19(3):370-82. Pubmed: 27424782 DOI:S1934-5909(16)30154-0

Abstract

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.

Related Faculty

Wolfram Goessling, M.D., Ph.D.

Wolfram Goessling uses the zebrafish model to study regulators of liver development and to explore endodermal progenitor cell specification, organ differentiation, and growth.