Sphingosine-1-Phosphate Receptor Antagonism Enhances Proliferation and Migration of Engrafted Neural Progenitor Cells in a Model of Viral-Induced Demyelination

Abstract

The oral drug FTY720 affects sphingosine-1-phosphate (S1P) signaling on targeted cells that bear the S1P receptors S1P1, S1P3, S1P4, and S1P5. We examined the effect of FTY720 treatment on the biology of mouse neural progenitor cells (NPCs) after transplantation in a viral model of demyelination. Intracerebral infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) resulted in an acute encephalomyelitis, followed by demyelination similar in pathology to the human demyelinating disease, multiple sclerosis. We have previously reported that intraspinal transplantation of mouse NPCs into JHMV-infected animals resulted in selective colonization of demyelinated lesions, preferential differentiation into oligodendroglia accompanied by axonal preservation, and increased remyelination. Cultured NPCs expressed transcripts for S1P receptors S1P1, S1P2, S1P3, S1P4, and S1P5. FTY720 treatment of cultured NPCs resulted in increased mitogen-activated protein kinase phosphorylation and migration after exposure to the chemokine CXCL12. Administration of FTY720 to JHMV-infected mice resulted in enhanced migration and increased proliferation of transplanted NPCs after spinal cord engraftment. FTY720 treatment did not improve clinical disease, diminish neuroinflammation or the severity of demyelination, nor increase remyelination. These findings argue that FTY720 treatment selectively increases NPC proliferation and migration but does not either improve clinical outcome or enhance remyelination after transplantation into animals in which immune-mediated demyelination is initiated by the viral infection of the central nervous system. Intracranial infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV) results in an acute encephalomyelitis, followed by chronic demyelination characterized by viral persistence within the central nervous system (CNS), axonal damage, and demyelination.1e7 Previous studies from our laboratory have used the JHMV model of neuroinflammation-mediated demyelination to evaluate the therapeutic benefit of mouse neural progenitor cell (NPC) engraftment on remyelination.8e10 Transplantation of mouse NPCs into the spinal cords of JHMV-infected mice results in extensive migration and colonization of areas of white matter damage and preferential differentiation into oligodendroglia.8e10 Engrafted NPCs physically engage damaged axons, and this ultimately leads to increased axonal integrity that correlates with remyelination. 8,11 These findings, along with others,

Effects of FTY720 (Fingolimod) on Proliferation, Differentiation, and Migration of Brain‐Derived Neural Stem Cells

“…However, we failed to observe similar results in cultured NSCs, as no significant differences were found among groups of β -tubulin III positive cells. Our conclusion was supported by a study on a viral-induced demyelination mice model [16]. And no neuron differentiation on embryonic hippocampal NSCs has also been reported recently [25].…”

“…However, more morphological matured oligodendrocytes were seen in the higher dose FTY720 groups. The different results among groups might be because of people using different originated NSCs or diseases models [1, 16, 29–31]. …”

“…To examine the effect of FTY720 (FTY720-P: FTY720 phosphate: Cayman, USA) [16], NSCs were divided into four groups according to the concentration of FTY-720 (0 nM, 1 nM, 10 nM, and 100 nM, diluted in DMSO) in basic culture medium within (for differentiation) or without (for CCK-8 testing and the sphere number counting) 10% fetal bovine serum (HyClone, Thermo, USA). 0 nM FTY720 was recognized as the control group.…”

Disrupted CXCR2 Signaling in Oligodendroglia Lineage Cells Enhances Myelin Repair in a Viral Model of Multiple Sclerosis

“…In all experimental groups, the g ratios averaged ϳ0.8, indicating normal myelinated axons in the spinal cord ( Fig. 3E and F) (55)(56)(57). These findings argue that inducible deletion of CXCR2 in oligodendroglia lineage cells in young (4-week-old) mice does not affect the myelin content in a nondisease state.…”

“…Our findings are consistent with those of Kerstetter et al (58), who showed that treatment of mice with MOG 35-55 -induced EAE with small-molecule antagonists specific for CXCR2 resulted in improved motor skills that correlated with diminished white matter damage associated with enhanced re-myelination, arguing that CXCR2 may be a relevant therapeutic target for the treatment combination with Luxol fast blue (LFB), and between 4 and 8 sections per mouse were analyzed. Areas of total white matter and demyelinated white matter were determined with ImageJ software, and demyelination was scored as the percentage of total demyelination from the spinal cord sections analyzed (55,67,70).…”