Chemokines promote quiescence and survival of human neural progenitor cells.
Many cell types in the brain express chemokines and chemokine receptors under homeostatic conditions, arguing for a role of these proteins in normal brain processes. Because chemokines have been shown to regulate hematopoietic progenitor cell proliferation, we hypothesized that chemokines would regulate neural progenitor cell (NPC) proliferation as well. Here we show that chemokines activating CXCR4 or CCR3 reversibly inhibit NPC proliferation in isolated cells, neurospheres, and in hippocampal slice cultures. Cells induced into quiescence by chemokines maintain their multipotential ability to form both neurons and astrocytes. The mechanism of chemokine action appears to be a reduction of extracellular signal-related kinase phosphorylation as well as an increase in Reelin expression. The inhibitory effects of chemokines are blocked by heparan sulfate and apolipoprotein E3 but not apolipoprotein E4, suggesting a regulatory role of these molecules on the effects of chemokines. Additionally, we found that the chemokine fractalkine promotes survival of NPCs. In addition to their role in chemotaxis, chemokines affect both the survival and proliferation of human NPCs in vitro. The presence of constitutively expressed chemokines in the brain argues that under homeostatic conditions, chemokines promote survival but maintain NPCs in a quiescent state. Our studies also suggest a link between inflammatory chemokine production and the inhibition of neurogenesis.
Krathwohl
Mitchell D
MD
Department of Medicine, Center for Immunology and Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, USA. krath001@umn.edu
Kaiser
Jodi L
JL
D053318:Apolipoprotein E3; D001057:Apolipoproteins E / Q000378:metabolism / Q000494:pharmacology; D001253:Astrocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D015816:Cell Adhesion Molecules, Neuronal / Q000378:metabolism; D018929:Cell Culture Techniques / Q000379:methods*; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002455:Cell Division / Q000187:drug effects* / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects* / Q000276:immunology; D054428:Chemokine CX3CL1; D018925:Chemokines / Q000276:immunology / Q000494:pharmacology*; D020523:Chemokines, CX3C / Q000276:immunology / Q000494:pharmacology; D004660:Encephalitis / Q000276:immunology; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005333:Fetus; D006497:Heparan Sulfate / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D008565:Membrane Proteins / Q000276:immunology / Q000494:pharmacology; D009419:Nerve Tissue Proteins; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D010766:Phosphorylation / Q000187:drug effects; D054397:Receptors, CCR3; D019718:Receptors, CXCR4 / Q000187:drug effects / Q000276:immunology; D019707:Receptors, Chemokine / Q000187:drug effects / Q000276:immunology; D000091042:Reelin Protein; D012697:Serine Endopeptidases; D013234:Stem Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology
D053318:Apolipoprotein E3; D001057:Apolipoproteins E; D015816:Cell Adhesion Molecules, Neuronal; D054428:Chemokine CX3CL1; D018925:Chemokines; D020523:Chemokines, CX3C; D016326:Extracellular Matrix Proteins; D006497:Heparan Sulfate; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D054397:Receptors, CCR3; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D000091042:Reelin Protein; D012697:Serine Endopeptidases; C515350:CCR3 protein, human; C515538:CX3CL1 protein, human; C000717127:RELN protein, human