title: GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement.
abstract: Regulation of hematopoietic stem and progenitor cell (HSPC) steady-state egress from the bone marrow (BM) to the circulation is poorly understood. While glycogen synthase kinase-3β (GSK3β) is known to participate in HSPC proliferation, we revealed an unexpected role in the preferential regulation of CXCL12-induced migration and steady-state egress of murine HSPCs, including long-term repopulating HSCs, over mature leukocytes. HSPC egress, regulated by circadian rhythms of CXCL12 and CXCR4 levels, correlated with dynamic expression of GSK3β in the BM. Nevertheless, GSK3β signaling was CXCL12/CXCR4 independent, suggesting that synchronization of both pathways is required for HSPC motility. Chemotaxis of HSPCs expressing higher levels of GSK3β compared with mature cells was selectively enhanced by stem cell factor-induced activation of GSK3β. Moreover, HSPC motility was regulated by norepinephrine and insulin-like growth factor-1 (IGF-1), which increased or reduced, respectively, GSK3β expression in BM HSPCs and their subsequent egress. Mechanistically, GSK3β signaling promoted preferential HSPC migration by regulating actin rearrangement and microtubuli turnover, including CXCL12-induced actin polarization and polymerization. Our study identifies a previously unknown role for GSK3β in physiological HSPC motility, dictating an active, rather than a passive, nature for homeostatic egress from the BM reservoir to the blood circulation.
authors.affiliation: Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Kfir
authors.initials: K
authors.lastname: Lapid
authors.forename: Tomer
authors.initials: T
authors.lastname: Itkin
authors.forename: Gabriele
authors.initials: G
authors.lastname: D'Uva
authors.forename: Yossi
authors.initials: Y
authors.lastname: Ovadya
authors.forename: Aya
authors.initials: A
authors.lastname: Ludin
authors.forename: Giulia
authors.initials: G
authors.lastname: Caglio
authors.forename: Alexander
authors.initials: A
authors.lastname: Kalinkovich
authors.forename: Karin
authors.initials: K
authors.lastname: Golan
authors.forename: Ziv
authors.initials: Z
authors.lastname: Porat
authors.forename: Massimo
authors.initials: M
authors.lastname: Zollo
authors.forename: Tsvee
authors.initials: T
authors.lastname: Lapidot
mesh_terms: D008841:Actin Cytoskeleton / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology; D002633:Chemotaxis; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D000071679:Glycogen Synthase Kinase 3 beta; D006412:Hematopoietic Stem Cells / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000502:physiology; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008870:Microtubules / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D015398:Signal Transduction; D019089:Stem Cell Factor / Q000502:physiology
chemical_list: C514936:CXCR4 protein, mouse; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; D047428:Protein Kinase Inhibitors; D019718:Receptors, CXCR4; D019089:Stem Cell Factor; D007334:Insulin-Like Growth Factor I; D017526:Receptor, IGF Type 1; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3