title: The neurotransmitter GABA is a potent inhibitor of the stromal cell-derived factor-1alpha 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-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.
authors.affiliation: Institute of Immunology, Witten/Herdecke University, 58448 Witten, Germany.
authors.forename: Jeanette
authors.initials: J
authors.lastname: Seidel
authors.forename: Bernd
authors.initials: B
authors.lastname: Niggemann
authors.forename: Michael
authors.initials: M
authors.lastname: Punzel
authors.forename: Johannes
authors.initials: J
authors.lastname: Fischer
authors.forename: Kurt S
authors.initials: KS
authors.lastname: Zänker
authors.forename: Thomas
authors.initials: T
authors.lastname: Dittmar
mesh_terms: D000071916:AC133 Antigen; D053687:Adult Stem Cells / Q000166:cytology* / Q000187:drug effects*; D015703:Antigens, CD / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D015220:Calcium Channels / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects*; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000494:pharmacology*; D005434:Flow Cytometry; D006023:Glycoproteins / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D006801:Humans; D007091:Image Processing, Computer-Assisted; D018377:Neurotransmitter Agents / Q000494:pharmacology; D010455:Peptides / Q000378:metabolism*; D018080:Receptors, GABA-B / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology*
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D015220:Calcium Channels; D054377:Chemokine CXCL12; D006023:Glycoproteins; D018377:Neurotransmitter Agents; C000606023:PROM1 protein, human; D010455:Peptides; D018080:Receptors, GABA-B; D005680:gamma-Aminobutyric Acid; D002118:Calcium