title: LINGO-1-Fc-Transduced Neural Stem Cells Are Effective Therapy for Chronic Stage Experimental Autoimmune Encephalomyelitis.
abstract: 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.
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.|College of Life Sciences, Shaanxi Normal University, Xi'an, China.
authors.forename: Xing
authors.identifier: 0000-0001-9084-4503
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.|College of Life Sciences, Shaanxi Normal University, Xi'an, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.|College of Life Sciences, Shaanxi Normal University, Xi'an, China.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yan
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.affiliation: Institute of Brain Science, Department of Neurology, Shanxi Datong University Medical School, Datong, China.
authors.forename: Cun-Gen
authors.initials: CG
authors.lastname: Ma
authors.affiliation: Department of Neuroscience, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Jeannie
authors.initials: J
authors.lastname: Chin
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Curtis
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA.
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, PA, USA. Guang-Xian.Zhang@jefferson.edu.
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D019898:Autocrine Communication; D001369:Axons / Q000378:metabolism; D002452:Cell Count; D002454:Cell Differentiation; D002908:Chronic Disease; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D005260:Female; D008565:Membrane Proteins / Q000378:metabolism*; D008810:Mice, Inbred C57BL; D004676:Myelin Basic Protein / Q000378:metabolism; D009243:NAD / Q000378:metabolism; D058953:Neural Stem Cells / Q000378:metabolism* / Q000637:transplantation*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009836:Oligodendroglia / Q000378:metabolism; D019899:Paracrine Communication; D011961:Receptors, Fc / Q000378:metabolism*; D020127:Recovery of Function; D000074586:Remyelination; D056565:Sirtuin 2 / Q000378:metabolism; D033581:Stem Cell Transplantation; D014161:Transduction, Genetic
chemical_list: D008565:Membrane Proteins; D004676:Myelin Basic Protein; D011961:Receptors, Fc; D009243:NAD; D056565:Sirtuin 2
keywords: Experimental autoimmune encephalomyelitis; LINGO-1-Fc; Neural stem cells; Oligodendrocytes; Regeneration