GSK3β Signaling Regulates the Motility of Hematopoietic Progenitors Via Prune.

Abstract 1553

One of the hallmarks of hematopoietic stem and progenitor cells (HSPC) is their motility. In steady state, HSPC are mostly retained in the bone marrow (BM), allowing ongoing hematopoiesis, concomitantly with slow release to the circulation as part of homeostasis and host defense mechanisms. While stress-induced recruitment and clinical mobilization processes are extensively studied, steady state egress mechanisms are poorly understood. In this study, we demonstrate that inhibition of Glycogen Synthase Kinase 3b (GSK3β) directly or via upstream Insulin-like Growth Factor-1 (IGF-1) signaling limited murine HSPC egress to the circulation. Indeed, inhibition of GSK3β resulted in reduced HSPC migration capacity towards a gradient of the chemokine stromal derived factor-1 (SDF-1, also termed CXCL12) in vitro and was found to reduce HSPC mobilization by IGF-1 receptor antagonist treatment. Interestingly, GSK3β signaling also regulated SDF-1 transcription by BM stromal cells in vitro and in vivo, probably as part of HSPC maintenance, since murine CXCR4 signaling is essential for hematopoietic stem cell quiescence. We revealed that the involvement of GSK3β in directional HSPC motility is mediated by the downstream phosphodiesterase Prune. Prune, which is over-expressed in several human cancers, was recently found to localize in focal adhesion sites, promoting the motility of malignant cells. Herein, we show that Prune is also expressed in normal leukocytes, including HSPC. Accordingly, inhibition of Prune resulted in reduced SDF-1 induced migration of murine HSPC in vitro as well as reduced steady state egress in vivo. Prune activity was also shown to regulate the actin cytoskeleton by contributing to its polymerization. In general, highly regulated actin turnover is essential for spontaneous and directional motility mechanisms. Altogether, we present GSK3β and Prune as novel players in physiological HSPC motility, dictating an active rather than passive nature for steady state egress from the BM reservoir to the blood circulation as part of homeostasis.