Antagonism of Sphingosine 1-Phosphate Receptor-2 Enhances Migration of Neural Progenitor Cells Toward an Area of Brain Infarction

Abstract

Background and Purpose-We have previously shown that the sphingosine 1-phosphate (S1P)/S1P receptor-1 (S1P 1 R) axis contributes to the migration of transplanted neural progenitor cells (NPCs) toward areas of spinal cord injury. In the current study, we examined a strategy to increase endogenous NPC migration toward the injured central nervous system to modify S1PR. Methods-S1P concentration in the ischemic brain was measured in a mouse thrombosis model of the middle cerebral artery. NPC migration in vitro was assessed by a Boyden chamber assay. Endogenous NPC migration toward the insult was evaluated after ventricular administration of the S1P 2 R antagonist JTE-013. Results-The concentration of S1P in the brain was increased after ischemia and was maximal 14 days after the insult. The increase in S1P in the infarcted brain was primarily caused by accumulation of microglia at the insult. Mouse NPCs mainly expressed S1P 1 R and S1P 2 R as S1PRs, and S1P significantly induced the migration of NPCs in vitro through activation of S1P 1 R. However, an S1P 1 R agonist failed to have any synergistic effect on S1P-mediated NPC migration, whereas pharmacologic or genetic inhibition of S1P 2 R by JTE-013 or short hairpin RNA expression enhanced S1P-mediated NPC migration but did not affect proliferation and differentiation. Interestingly, administration of JTE-013 into a brain ventricle significantly enhanced endogenous NPC migration toward the area of ischemia. Conclusions-Our findings suggest that S1P is a chemoattractant for NPCs released from an infarcted area and regulation of S1P 2 R function further enhances the migration of NPCs toward a brain infarction. (Stroke. 2008;39:3411-3417.)

Rho/ROCK pathway is essential to the expansion, differentiation, and morphological rearrangements of human neural stem/progenitor cells induced by lysophosphatidic acid

“…Our data also suggest that neurogenesis may be enhanced by blockers of LPA signaling, such as LPA antibodies that we recently demonstrated were able to abolish LPA's effect on human NS/PCs in vitro and improve neuronal survival and functional recovery following spinal cord injury in vivo ( 80 ). Such a mechanism has already been proved with sphingosine-1-phosphate, as blocking its signaling enhances endogenous NS/PC migration to the injury site following trauma ( 81 ).…”

An update on the biology of sphingosine 1-phosphate receptors

“…S1P regulates embryonic nervous system development, as the neuroepithelial layers of the developing telencephalon in S1pr1 Ϫ / Ϫ embryos have signifi cantly increased apoptosis and decreased mitosis ( 127 ). S1P 2 may also play a role in regulating neural progenitors, as postischemic administration of the S1P 2 antagonist JTE-013 or short hairpin RNA against S1P 2 signifi cantly increased progenitor migration to the ischemic region ( 128 ). This indicates that S1P 2 may repel neural progenitors from areas of high S1P concentration in the same manner as it regulates macrophage migration ( 102 ).…”

Sphingolipids in cardiovascular and cerebrovascular systems: Pathological implications and potential therapeutic targets

“…However, S1P in the brain was increased thereafter and reached a maximum 14 d after the insult. Upregulation of S1P was observed at the infarct border zone and at the infarct core, and mostly colocalized to microglia and some astrocytes, indicating that microglia may be the main source of S1P production in ischemic brain [104] . Moreover, the S1P regulating enzymes SphKs show differential tissue expression patterns and different subcellular localization [72] .…”

“…There is also evidence that S1P may act as a proximal trigger of cerebroprotection (both neuronal and vascular) through activation of signaling molecules such as endothelial nitric oxide synthase [102] . In models of stroke, Kimura et al [104] found that S1P concentrations in the brain were significantly decreased 3 d after ischemia. However, S1P in the brain was increased thereafter and reached a maximum 14 d after the insult.…”

“…FTY720 is phosphorylated by SphK, mainly by SphK2 [73,111] , into the active compound phospho-FTY720, which then acts on 4 of the 5 known S1P receptor subtypes (S1P1, S1P3, S1P4, S1P5), and shows neuroprotective effect against many central nervous system disease including cerebral ischemia [73,[112][113][114][115] . Mechanisms include regulation of myelination and microglial activation following injury, proliferation and migration of neural precursor cells toward injury sites, and potentiation of growth-factor regulated neuronal differentiation, survival, and process extension, and also antiapoptotic and anti-inflammatory pathways [104,113,[115][116][117][118][119] . FTY720 also exerts immunomodulatory actions by affecting lymphocyte production, trafficking, and apoptosis through S1P receptors which induces a depletion of circulating lymphocytes by preventing the egress of lymphocytes from the lymph nodes.…”