GSK3β regulates physiological migration of stem/progenitor cells via cytoskeletal rearrangement
Kfir Lapid, … , Massimo Zollo, Tsvee Lapidot
Kfir Lapid, … , Massimo Zollo, Tsvee Lapidot
Published March 8, 2013
Citation Information: J Clin Invest. 2013;123(4):1705-1717. https://doi.org/10.1172/JCI64149.
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Research Article Hematology Article has an altmetric score of 13

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

Kfir Lapid, Tomer Itkin, Gabriele D’Uva, Yossi Ovadya, Aya Ludin, Giulia Caglio, Alexander Kalinkovich, Karin Golan, Ziv Porat, Massimo Zollo, Tsvee Lapidot

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Figure 9

Flow chart shows how GSK3β signaling cooperates with CXCL12/CXCR4 signaling in murine HSPCs by governing their preferential and directional motility.

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Flow chart shows how GSK3β signaling cooperates with CXCL12/CXCR4 signal...
At ZT5, GSK3β expression is at its peak as is the number of circulating HSPCs, whereas at ZT13, GSK3β expression is at its lowest point, as is the number of circulating HSPCs. GSK3β inhibition by BIO-A rapidly impairs HSPC steady-state egress and migratory potential. NE induces rapid mobilization of HSPCs and enhances their motility, demonstrating upregulated GSK3β expression. IGF-1 administration for 1 week limits the egress of HSPCs and reduces their motility, demonstrating downregulated GSK3β expression. PQ401, which is an IGF-1R antagonist, induces rapid HSPC mobilization in a GSK3β-dependent manner. In vitro SCF treatment enhances HSPC migratory capacity, demonstrating upregulated GSK3β expression. GSK3β signaling thereby promotes HSPC motility by controlling the rearrangement of cytoskeletal machinery (i.e., control over actin and MT dynamics). Short-term denotes hours; long-term denotes days.