title: The Central Nervous System Regulates Embryonic HSPC Production via Stress-Responsive Glucocorticoid Receptor Signaling.
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.
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Wanda
authors.initials: W
authors.lastname: Kwan
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: Cortes
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Isaura
authors.initials: I
authors.lastname: Frost
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Virginie
authors.initials: V
authors.lastname: Esain
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Lindsay N
authors.initials: LN
authors.lastname: Theodore
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Sarah Y
authors.initials: SY
authors.lastname: Liu
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Nadine
authors.initials: N
authors.lastname: Budrow
authors.affiliation: Brigham and Women's Hospital and Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA.
authors.forename: Wolfram
authors.initials: W
authors.lastname: Goessling
authors.affiliation: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA; Harvard Stem Cell Institute, Harvard University, Cambridge, MA 02138, USA. Electronic address: tnorth@bidmc.harvard.edu.
authors.forename: Trista E
authors.initials: TE
authors.lastname: North
mesh_terms: D000818:Animals; D002452:Cell Count; D015687:Cell Hypoxia / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002490:Central Nervous System / Q000378:metabolism*; D004625:Embryo, Nonmammalian / Q000187:drug effects / Q000378:metabolism; D053595:Embryonic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D005473:Fluoxetine / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism*; D059326:Serotonergic Neurons / Q000187:drug effects / Q000378:metabolism; D012701:Serotonin / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects; D013564:Sympathetic Nervous System / Q000187:drug effects / Q000378:metabolism; D014365:Tryptophan Hydroxylase / Q000378:metabolism; D015027:Zebrafish / Q000196:embryology
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011965:Receptors, Glucocorticoid; D005473:Fluoxetine; D012701:Serotonin; D014365:Tryptophan Hydroxylase