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Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity.

ABSTRACT: Treatment of chronic neurodegenerative diseases such as multiple sclerosis (MS) remains a major challenge. Here we genetically engineer neural stem cells (NSCs) to produce a triply therapeutic cocktail comprising IL-10, NT-3, and LINGO-1-Fc, thus simultaneously targeting all mechanisms underlie chronicity of MS in the central nervous system (CNS): persistent inflammation, loss of trophic support for oligodendrocytes and neurons, and accumulation of neuroregeneration inhibitors. After transplantation, NSCs migrated into the CNS inflamed foci and delivered these therapeutic molecules in situ. NSCs transduced with one, two, or none of these molecules had no or limited effect when injected at the chronic stage of experimental autoimmune encephalomyelitis; cocktail-producing NSCs, in contrast, mediated the most effective recovery through inducing M2 macrophages/microglia, reducing astrogliosis, and promoting axonal integrity and endogenous oligodendrocyte/neuron differentiation. These engineered NSCs simultaneously target major mechanisms underlying chronicity of multiple sclerosis (MS) and encephalomyelitis (EAE), thus representing a novel and potentially effective therapy for the chronic stage of MS, for which there is currently no treatment available.

SUBMITTER: Li X

PROVIDER: S-EPMC5023377 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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RETRACTED: Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity

Li Xing X Zhang Yuan Y Yan Yaping Y Ciric Bogoljub B Ma Cun-Gen CG Gran Bruno B Curtis Mark M Rostami Abdolmohamad A Zhang Guang-Xian GX

Molecular therapy : the journal of the American Society of Gene Therapy 20160516 8

This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the editor-in-chief. Similarities were found between images in this article and a previously published article in Scientific Reports (Zhang et al., 2015, Sci. Rep. 30, 17407, https://doi.org/10.1038/srep17407). Similarities were also found between images within this article. These concerns were initially reported i ...[more]

PMID: 27203442

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Project description:Leptomeningeal inflammation in multiple sclerosis is associated with worse clinical outcomes and greater cortical pathology. Despite progress in identifying this process in multiple sclerosis patients using post-contrast fluid-attenuated inversion recovery imaging, early trials attempting to target meningeal inflammation have been unsuccessful. There is a lack of appropriate model systems to screen potential therapeutic agents targeting meningeal inflammation. We utilized ultra-high field (11.7 T) MRI to perform post-contrast imaging in SJL/J mice with experimental autoimmune encephalomyelitis induced via immunization with proteolipid protein peptide (PLP139-151) and complete Freund's adjuvant. Imaging was performed in both a cross-sectional and longitudinal fashion at time points ranging from 2 to 14 weeks post-immunization. Following imaging, we euthanized animals and collected tissue for pathological evaluation, which revealed dense cellular infiltrates corresponding to areas of contrast enhancement involving the leptomeninges. These areas of meningeal inflammation contained B cells (B220+), T cells (CD3+) and myeloid cells (Mac2+). We also noted features consistent with tertiary lymphoid tissue within these areas, namely the presence of peripheral node addressin-positive structures, C-X-C motif chemokine ligand-13 (CXCL13)-producing cells and FDC-M1+ follicular dendritic cells. In the cortex adjacent to areas of meningeal inflammation we identified astrocytosis, microgliosis, demyelination and evidence of axonal stress/damage. Since areas of meningeal contrast enhancement persisted over several weeks in longitudinal experiments, we utilized this model to test the effects of a therapeutic intervention on established meningeal inflammation. We randomized mice with evidence of meningeal contrast enhancement on MRI scans performed at 6 weeks post-immunization, to treatment with either vehicle or evobrutinib [a Bruton tyrosine kinase (BTK) inhibitor] for a period of 4 weeks. These mice underwent serial imaging; we examined the effect of treatment on the areas of meningeal contrast enhancement and noted a significant reduction in the evobrutinib group compared to vehicle (30% reduction versus 5% increase; P = 0.003). We used ultra-high field MRI to identify areas of meningeal inflammation and to track them over time in SJL/J mice with experimental autoimmune encephalomyelitis, and then used this model to identify BTK inhibition as a novel therapeutic approach to target meningeal inflammation. The results of this study provide support for future studies in multiple sclerosis patients with imaging evidence of meningeal inflammation.

Dataset Information

Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity.

Publications

RETRACTED: Neural Stem Cells Engineered to Express Three Therapeutic Factors Mediate Recovery from Chronic Stage CNS Autoimmunity

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