title: Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields.
abstract: The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF-enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization. Peripheral sympathetic nerve neurons express the G-CSF receptor and ex vivo stimulation of peripheral sympathetic nerve neurons with G-CSF reduced NE reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. Based on these data, we investigated the NE reuptake inhibitor desipramine in HSPC mobilization. Whereas desipramine did not by itself elicit circulating HSPCs, it increased G-CSF-triggered mobilization efficiency significantly and rescued mobilization in a model mimicking "poor mobilizers." Therefore, these data suggest that blockade of NE reuptake may be a novel therapeutic target to increase stem cell yield in patients.
authors.affiliation: Ruth L. and David S. Gottesman Institute for Stem Cell Biology and Regenerative Medicine, Albert Einstein College of Medicine, New York, NY 10461, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Lucas
authors.forename: Ingmar
authors.initials: I
authors.lastname: Bruns
authors.forename: Michela
authors.initials: M
authors.lastname: Battista
authors.forename: Simon
authors.initials: S
authors.lastname: Mendez-Ferrer
authors.forename: Claire
authors.initials: C
authors.lastname: Magnon
authors.forename: Yuya
authors.initials: Y
authors.lastname: Kunisaki
authors.forename: Paul S
authors.initials: PS
authors.lastname: Frenette
mesh_terms: D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002478:Cells, Cultured; D005455:Fluorescent Antibody Technique; D016179:Granulocyte Colony-Stimulating Factor; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009638:Norepinephrine / Q000378:metabolism*; D013564:Sympathetic Nervous System / Q000166:cytology / Q000378:metabolism
chemical_list: D016179:Granulocyte Colony-Stimulating Factor; D009638:Norepinephrine