title: Signaling through three chemokine receptors triggers the migration of transplanted neural precursor cells in a model of multiple sclerosis.
abstract: Multiple sclerosis (MS) is a multifocal disease, and precursor cells need to migrate into the multiple lesions in order to exert their therapeutic effects. Therefore, cell migration is a crucial element in regenerative processes in MS, dictating the route of delivery, when cell transplantation is considered. We have previously shown that inflammation triggers migration of multi-potential neural precursor cells (NPCs) into the white matter of experimental autoimmune encephalomyelitis (EAE) rodents, a widely used model of MS. Here we investigated the molecular basis of this attraction. NPCs were grown from E13 embryonic mouse brains and transplanted into the lateral cerebral ventricles of EAE mice. Transplanted NPC migration was directed by three tissue-derived chemokines. Stromal cell-derived factor-1α, monocyte chemo-attractant protein-1 and hepatocyte growth factor were expressed in the EAE brain and specifically in microglia and astrocytes. Their cognate receptors, CXCR4, CCR2 or c-Met were constitutively expressed on NPCs. Selective blockage of CXCR4, CCR2 or c-Met partially inhibited NPC migration in EAE brains. Blocking all three receptors had an additive effect and resulted in profound inhibition of NPC migration, as compared to extensive migration of control NPCs. The inflammation-triggered NPC migration into white matter tracts was dependent on a motile NPC phenotype. Specifically, depriving NPCs from epidermal growth factor (EGF) prevented the induction of glial commitment and a motile phenotype (as indicated by an in vitro motility assay), hampering their response to neuroinflammation. In conclusion, signaling via three chemokine systems accounts for most of the inflammation-induced, tissue-derived attraction of transplanted NPCs into white matter tracts during EAE.
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Mikhal E
authors.initials: ME
authors.lastname: Cohen
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Nina
authors.initials: N
authors.lastname: Fainstein
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Medical Center, Jerusalem, Israel; Leslie and Michael Gaffin Centre for Neuro-Oncology, Hadassah University Medical Center, Jerusalem, Israel.
authors.forename: Iris
authors.initials: I
authors.lastname: Lavon
authors.affiliation: Department of Neurology, The Agnes Ginges Center for Human Neurogenetics, Hadassah University Medical Center, Jerusalem, Israel. Electronic address: tamir@hadassah.org.il.
authors.forename: Tamir
authors.initials: T
authors.lastname: Ben-Hur
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001253:Astrocytes / Q000378:metabolism; D002478:Cells, Cultured; D002552:Cerebral Ventricles / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D018932:Chemokine CCL2 / Q000378:metabolism; D054377:Chemokine CXCL12 / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000601:surgery*; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008810:Mice, Inbred C57BL; D017628:Microglia / Q000378:metabolism; D058953:Neural Stem Cells / Q000276:immunology / Q000378:metabolism / Q000637:transplantation*; D010641:Phenotype; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D054390:Receptors, CCR2 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D066127:White Matter / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
chemical_list: D000906:Antibodies; C514936:CXCR4 protein, mouse; C491768:Ccl2 protein, mouse; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse; C553307:HGF protein, mouse; D018836:Inflammation Mediators; D054390:Receptors, CCR2; D019718:Receptors, CXCR4; D019707:Receptors, Chemokine; D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met