Use of engineered bone marrow stem cells to deliver brain derived neurotrophic factor under the control of a tetracycline sensitive response element in experimental allergic encephalomyelitis

Makar, Tapas K.; Nimmagadda, Vamshi K.C.; Patibandla, Gopi K.; Le, Toby; Judge, Susan I.V.; Trisler, David

doi:10.1016/j.jneuroim.2012.07.005

Cited by 9 publications

(11 citation statements)

References 51 publications

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“…Seven-micron-thick sections were stained with H&E (to detect inflammatory infiltrates) and Luxol Fast Blue (LFB; for demyelination), following standard protocols for conventional light microscopy. Analysis of inflammation and demyelination was performed, as described previously (32), in a blinded manner.…”

Section: Detection Of Tissue Pathologymentioning

confidence: 99%

Overexpression of SIRT1 Protein in Neurons Protects against Experimental Autoimmune Encephalomyelitis through Activation of Multiple SIRT1 Targets

Nimmagadda

Bever

Vattikunta

et al. 2013

The Journal of Immunology

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116

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Treatment of experimental autoimmune encephalomyelitis (EAE) with Resveratrol, an activator of Sirtuin 1 (SIRT1), reduces disease severity. This suggested that activators of SIRT1, a highly conserved nicotinamide adenine dinucleotide (NAD)-dependent protein deacetylase, might have immune-modulating or neuroprotective therapeutic effects in EAE. Previously, we showed that SIRT1 expression increases in EAE, suggesting that it is an adaptive response. In this study, we investigated the potential function of SIRT1 in regulating EAE using SIRT1 overexpressing mice. The current studies examine potential neuroprotective and immunomodulatory effects of SIRT1 overexpression in chronic EAE induced by immunization of C57Bl/6 mice with myelin oligodendrocyte glycoprotein peptide (MOG35-55). SIRT1 suppressed EAE clinical symptoms compared with wild-type EAE mice and prevented or altered the phenotype of inflammation in spinal cords; as a result, demyelination and axonal injury were reduced. Significant neuroprotective effects were observed, with fewer apoptotic cells found in the spinal cords of SIRT1 overexpressing EAE mice; associated with increased brain-derived neurotrophic factor (BDNF) and NAD levels. Earlier, we showed that BDNF and NAD play crucial neuroprotective roles in EAE. These results suggest that SIRT1 reduces neuronal loss in this chronic demyelinating disease model and that this is associated with a reduction in inflammation.

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Section: Detection Of Tissue Pathologymentioning

confidence: 99%

Overexpression of SIRT1 Protein in Neurons Protects against Experimental Autoimmune Encephalomyelitis through Activation of Multiple SIRT1 Targets

Nimmagadda

Bever

Vattikunta

et al. 2013

The Journal of Immunology

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116

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“…Through binding to the TrkB receptor, BDNF induces NAMPT, a rate-limiting enzyme involved in the conversion of nicotinamide into NAD [44]. NAD then induces Sirt2, an endogenous neuroprotective factor that can promote OPC differentiation [42,43].…”

Section: Discussionmentioning

confidence: 99%

“…We therefore determined the effect of LINGO-1-Fc-NSC treatment on molecules downstream of BDNF, including nicotinamide adenine dinucleotide (NAD) and Sirt [42][43][44]. NAD concentration was significantly increased in the CNS of LINGO-1-Fc-NSC-treated EAE mice compared to ctrl-NSC-treated EAE mice (Fig.…”

Section: Enhanced Nad Production and Sirt2 Expression In Eae Mice Tramentioning

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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“…Delivery of BDNF using transformed bone marrow stem cells (BMSC) in mice is shown to have reduced clinical impairment compared to control mice receiving BMSC that did not produce BDNF (Makar et al, 2014). A reduction in inflammatory infiltrating cells; apoptotic cells, cleaved Caspase-3 staining is observed suggesting that BDNF reduces clinical severity, inflammation (Makar et al, 2012, 2014). Furthermore, we have shown that BDNF delivery increased SIRT1 expression in EAE animals (Makar et al 2012).…”

Section: Sirt1 – Ms and Eaementioning

confidence: 99%

“…A reduction in inflammatory infiltrating cells; apoptotic cells, cleaved Caspase-3 staining is observed suggesting that BDNF reduces clinical severity, inflammation (Makar et al, 2012, 2014). Furthermore, we have shown that BDNF delivery increased SIRT1 expression in EAE animals (Makar et al 2012). SIRT1 regulates BDNF expression via its epigenetic pathway of deacetylation of histones and other transcription factors (Smith et al, 2000; Tanny et al, 1999).…”

Section: Sirt1 – Ms and Eaementioning

confidence: 99%

SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review

Nimmagadda

Makar

Chandrasekaran

et al. 2017

Journal of Neuroimmunology

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Neurodegeneration is an important determinant of disability in multiple sclerosis (MS) but while currently approved treatments reduce inflammation, they have not been shown to reduce neurodegeneration. SIRT1, a NAD dependent protein deacetylase, has been implicated in the pathogenesis of neurodegeneration in neurological diseases including MS. We have studied the role of SIRT1 in experimental autoimmune encephalomyelitis (EAE) and found evidence for a neuroprotective role. In this review we summarize the most recent findings from the use of SIRT1 activators and SIRT1 overexpression in transgenic mice. These data support provide a rational for the use of SIRT1 activators in MS.

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Use of engineered bone marrow stem cells to deliver brain derived neurotrophic factor under the control of a tetracycline sensitive response element in experimental allergic encephalomyelitis

Cited by 9 publications

References 51 publications

Overexpression of SIRT1 Protein in Neurons Protects against Experimental Autoimmune Encephalomyelitis through Activation of Multiple SIRT1 Targets

Overexpression of SIRT1 Protein in Neurons Protects against Experimental Autoimmune Encephalomyelitis through Activation of Multiple SIRT1 Targets

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

SIRT1 and NAD+ precursors: Therapeutic targets in multiple sclerosis a review

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