The Neurotransmitter GABA Is a Potent Inhibitor of the Stromal Cell-Derived Factor-1αInduced Migration of Adult CD133⁺Hematopoietic Stem and Progenitor Cells

Abstract

The ability of hematopoietic stem and progenitor cells (HSPCs) to migrate is a prerequisite for bone marrow homing and tissue regeneration processes. Induction of HSPC migration is chiefly directed by stromal cell-derived factor-1alpha (SDF-1alpha). Considerably less is known about factors that terminate HSPC migration. Adult CD133(+) HSPCs were isolated from mobilized peripheral blood by immunomagnetic separation. Cell migration was assessed using the three-dimensional collagen matrix migration assay, which allows detailed migration analysis on a cell population and single-cell level. The SDF-1alpha-induced locomotory activity of CD133(+) cells was efficiently blocked by the neurotransmitter gamma-aminobutyric acid (GABA). GABA signaling was effected via the GABA(B)-receptor. This was verified by flow cytometry and cell migration studies using the specific GABA(A)-receptor and GABA(B)-receptor agonists isoguvacine and baclofen, respectively. Baclofen blocked SDF-1alpha-induced migration of CD133(+) cells. Flow cytometry-based calcium measurements revealed that GABA inhibits the SDF-1alpha-induced migration of CD133(+) cells by blocking the SDF-1alpha-induced calcium influx. Similar results were obtained with the specific calcium-release-activated calcium (CRAC) channel inhibitor BTP-2, which both blocked the SDF-1alpha-induced calcium influx and migration of CD133(+) cells. These results suggest that GABA(B)-receptor signaling modulates the activity of CRAC channels, whereby the mechanism in detail remains unclear. In summary, the neurotransmitter GABA is a potent blocker of the SDF-1alpha-induced migration of CD133(+) HSPCs from mobilized peripheral blood.

SDF and GABA interact to regulate axophilic migration of GnRH neurons

“…However, work in the hematopoietic system indicates that GABA can block SDF-1a-induced movement of adult mobilized hematopoietic stem and peripheral cells (Seidel et al, 2007). A series of experiments were performed to evaluate if there was synergistic or opposing activity between GABA and SDF-1 to modulate GnRH neuronal movement.…”

“…SDF-1, a chemokine, is involved in primordial germ cell migration (Blaser et al, 2005), migration of neural progenitors (via its receptor CXCR4) and axon growth and branching during development of the nervous system (Tran and Miller, 2003;Pujol et al, 2005). Recent work has shown that GABA and SDF-1 may act synergistically to alter cell movement (Seidel et al, 2007;Bhattacharyya et al, 2008). The molecular mechanisms of this interaction are still unclear, but the possible consequences of this event may have opposite effects on cellular behavior (Seidel et al, 2007;Bhattacharyya et al, 2008).…”

“…Recent work has shown that GABA and SDF-1 may act synergistically to alter cell movement (Seidel et al, 2007;Bhattacharyya et al, 2008). The molecular mechanisms of this interaction are still unclear, but the possible consequences of this event may have opposite effects on cellular behavior (Seidel et al, 2007;Bhattacharyya et al, 2008).…”

The importance of calcium in the regulation of megakaryocyte function

“…21 The same mechanism is responsible for promoting interaction with the ECM environment in different human cell types. 9,25 In order to investigate the role of Ca 2+ signaling in regulating ADP-dependent human Mk functions, we performed real-time measurements of intracellular Ca 2+ movements. We demonstrated an increase in [Ca 2+ ] i upon ADP stimulation in static conditions and a direct correlation between Ca 2+ signaling and Mk cytoskeleton remodeling under flow conditions.…”

“…The increase in cytosolic calcium concentration ([Ca 2+ ] i ) has been described to be required for interaction with the extracellular environment in different human cell types. 8,9 Interestingly, extracellular nucleotides and purinergic receptors are critically involved in mediating this interaction with changes in [Ca 2+ ] i . 10,11 Mks express all P2Y G-protein-coupled receptors (GPCRs) for purine and pyrimidine nucleotides 7 and all G-proteins coupled to Ca 2+ signaling activation.…”