The Neurotransmitter GABA Is a Potent Inhibitor of the Stromal Cell-Derived Factor-1 α Induced 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-1α (SDF-1α). 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-1α-induced locomotory activity of CD133⁺ cells was efficiently blocked by the neurotransmitter γ-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-1α-induced migration of CD133⁺ cells. Flow cytometry-based calcium measurements revealed that GABA inhibits the SDF-1α-induced migration of CD133⁺ cells by blocking the SDF-1α-induced calcium influx. Similar results were obtained with the specific calcium-release-activated calcium (CRAC) channel inhibitor BTP-2, which both blocked the SDF-1α-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-1α-induced migration of CD133⁺ HSPCs from mobilized peripheral blood.