Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis

Zhang, Jing; Zhang, Zheng Gang; Li, Yang; Ding, Xiaoshuang; Shang, Xia; Lü, Mei; Elias, Stanton B.; Chopp, Michael

doi:10.1016/j.nbd.2015.01.006

Cited by 87 publications

(70 citation statements)

References 60 publications

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“…27,49,50 In vivo studies demonstrated that FTY720 is effective at treating acute EAE by promoting OPC proliferation and differentiation and by stimulating the sonic hedgehog (Shh) signaling pathway. 51 These results, together with our findings, indicate that FTY720 has both anti-inflammatory and neuroregenerative effects.…”

Section: Discussionsupporting

confidence: 79%

“…45 Consistent with these findings, our in vitro results showed that low doses of FTY720 (%5 nM) are safe and have positive effects on NSC proliferation, driving NSCs to differentiate into greater numbers of neurons, OPCs, and OLGs but fewer astrocytes, while at high concentrations (e.g., 10 nM) FTY720 reduced numbers of OLGs and even induced OLG death. In in vivo studies, at the lower dosage (oral, 0.3 mg/kg/day) used in a previous report 51 and in our study, FTY720 treatment enhanced MBP expression and remyelination. These consistent results suggest that FTY720 induces OLG death only at high concentrations, while it promotes OLG differentiation at low concentrations (e.g., %5 nM in vitro and 0.3 mg/kg/day in vivo).…”

Section: Discussionsupporting

confidence: 65%

“…Then, 200 ng of pertussis toxin (List Biological Lab) were given intraperitoneally on days 0 and 2 post-immunization (p.i.). Clinical scores were assigned blindly by two researchers daily according to a 0-5 scale as follows: 51 1, limp tail or waddling gait with tail tonicity; 2, waddling gait with limp tail (ataxia); 2.5, ataxia with partial limb paralysis; 3, full paralysis of one limb; 3.5, full paralysis of one limb with partial paralysis of the second limb; 4, full paralysis of two limbs; 4.5, moribund; and 5, death. A relapse is defined as an increase in at least one clinical grade sustained for at least 2 consecutive days after animals have previously improved at least a full clinical grade and stabilized, while SP-EAE is defined as disease without remissions.…”

Section: Rr-eae and Sp-eae Induction And Treatmentmentioning

confidence: 99%

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Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Zhang

Ćirić

et al. 2017

Molecular Therapy

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Inflammatory demyelination and axonal damage of the CNS are hallmarks of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). Fingolimod (FTY720), the first FDA-approved oral medication for MS, suppresses acute disease but is less effective at the chronic stage, and whether it has a direct effect on neuroregeneration in MS and EAE remains unclear. Here we show that FTY720, at nanomolar concentrations, effectively protected survival of neural stem cells (NSCs) and enhanced their development into mature oligodendrocytes (OLGs) in vitro, primarily through the S1P3 and S1P5 receptors. In vivo, treatment with either FTY720 or NSCs alone had no effect on the secondary progressive stage of remitting-relapsing EAE, but a combination therapy with FTY720 and NSCs promoted significant recovery, including ameliorated clinical signs and CNS inflammatory demyelination, enhanced MBP synthesis and remyelination, inhibited axonal degeneration, and reduced astrogliosis. Moreover, FTY720 significantly improved incorporation and survival of transplanted NSCs in the CNS and drove their differentiation into more OLGs but fewer astrocytes, thus promoting remyelination and CNS repair processes in situ. Our data demonstrate a novel effect of FTY720 on NSC differentiation and remyelination, broadening its possible application to NSC-based therapy in the secondary progressive stage of MS.

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Section: Discussionsupporting

confidence: 79%

Section: Discussionsupporting

confidence: 65%

Section: Rr-eae and Sp-eae Induction And Treatmentmentioning

confidence: 99%

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Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Zhang

Ćirić

et al. 2017

Molecular Therapy

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“…Results were visualized by fluorescent microscopy (Nikon Eclipse E600; Nikon, Melville, NY) or confocal microscopy (Zeiss LSM 510; Carl Zeiss, Thornwood, NY). For quantification of HE, LFB, and MBP + , ten areas in the white matter of the lumbar spinal cord were selected [38].…”

Section: Histological Analysismentioning

confidence: 99%

LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis

Zhang

Yan

et al. 2016

Mol Neurobiol

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The chronic stage multiple sclerosis (MS), an inflammatory demyelinating disease of the central nervous system (CNS), remains refractory to current treatments. This refractory nature may be due to the fact that current treatments are primarily immunomodulatory, which prevent further demyelination but lack the capacity to promote remyelination. Several approaches, including transplantation of neural stem cells (NSCs) or antagonists to LINGO-1, a key part of the receptor complex for neuroregeneration inhibitors, have been effective in suppressing the acute stage of experimental autoimmune encephalomyelitis (EAE), an animal model of MS. However, their effect on the chronic stage EAE is not known. Here, we show that transplantation of NSCs had only a slight therapeutic effect when treatment started at the chronic stage of EAE (e.g., injected at day 40 postimmunization). However, NSCs engineered to produce LINGO-1-Fc, a soluble LINGO-1 antagonist, significantly promoted neurological recovery as demonstrated by amelioration of clinical signs, improvement in axonal integrity, and enhancement of oligodendrocyte maturation and neuron repopulation. Significantly enhanced NAD production and Sirt2 expression were also found in the CNS of mice treated with LINGO-1-Fc-producing NSC. Moreover, differentiation of LINGO-1-Fc-producing NSCs into oligodendrocytes in vitro was largely diminished by an NAMPT inhibitor, indicating that LINGO-1-Fc enhances the NAMPT/NAD/Sirt2 pathway. Together, our study establishes a CNS-targeted, novel LINGO-1-Fc delivery system using NSCs, which represents a novel and effective NSC-based gene therapy approach for the chronic stage of MS.

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“…However, whether FTY720's mode of action in MS is solely by regulating lymphocyte trafficking or if alternative mechanisms of immune regulation exist remains to be elucidated. Current studies suggest that FTY720 also regulates Th17 and Th1 development (6,23) and Th1 and Treg balance (23) and has direct effects on the CNS by modulating astrocytes (24) and oligodendrocytes (25,26).…”

Section: Introductionmentioning

confidence: 99%

Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation

Tsai¹,

Huang²,

Garris³

et al. 2016

JCI Insight

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Fingolimod treatment promotes proliferation and differentiation of oligodendrocyte progenitor cells in mice with experimental autoimmune encephalomyelitis

Cited by 87 publications

References 60 publications

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

Effect of Fingolimod on Neural Stem Cells: A Novel Mechanism and Broadened Application for Neural Repair

LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis

Effects of sphingosine-1-phosphate receptor 1 phosphorylation in response to FTY720 during neuroinflammation

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