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.

Neuroinflammatory signals enhance the immunomodulatory and neuroprotective properties of multipotent adult progenitor cells

“…Overall, these results point out the potential of rMAPC in transplantation experiments where inflammation is already established. Directed injection of NSCs within the CNS in the EAE model showed that inflammation triggered the migration of the transplanted cells towards the white matter tracts, with CXCL12α and CCL2 being important inflamed tissue-derived chemoattractive stimuli [ 70 ]. Furthermore, in other neuroinflammatory models, both peripheral- and CNS-targeted injected stem cells are being attracted by local sites of inflammation [ 71 ].…”

Systemic microbial TLR2 agonists induce neurodegeneration in Alzheimer’s disease mice

“…Single intracerebroventricular (ICV) injection of 15 μg, 25 μg, or 70 μg zymosan was performed using a stereotaxic device, at coordinates A = 0, L = 1, H = 2.5. For continuous delivery of zymosan, mice were implanted with Alzet pumps (1007D or 1004, according to manufacturer's instructions, and as previously described [3] enabling constitutive 1-week or 28 days release of 25 μg zymosan. Mice were sacrificed either 24 h, 3, 14 or 28 days following ICV injection or after 7 or 28 days of ICV pump by perfusion.…”

Stem Cells as Potential Targets of Polyphenols in Multiple Sclerosis and Alzheimer’s Disease

“…The CXCL8 expression in the CNS has been shown to drive recruitment of NSCs and OPCs to the sites of inflammation [ 105 ]. In EAE rodents it was observed that selectively blocking CXCR4, CCR2, or c-Met partially inhibited NPCs migration while blocking all three receptors had an additive effect and resulted in significant inhibition of NPCs migration in EAE brains [ 106 ]. In a diphtheria-toxin inducible genetic model for demyelination, Ascl1-mediated conversion of hippocampal NSCs into mature oligodendrocytes enhances remyelination [ 107 ].…”