title: Neurotrophin 3 transduction augments remyelinating and immunomodulatory capacity of neural stem cells.
abstract: Neural stem cells (NSCs) have therapeutic potential in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS); however, to date, their use has resulted in only limited clinical and pathological improvement. To enhance their therapeutic capacity, in the present study, we transduced bone marrow-derived NSCs (BM-NSCs) with neurotrophin 3 (NT-3), a potent neurotrophic factor that is both neuroprotective and immunomodulatory. We found that BM-NSCs transduced with NT-3 reduced central nervous system (CNS) inflammation and neurological deficits in ongoing EAE significantly more than conventional NSC therapy, and, in addition, had the following advantages: (i) enhanced BM-NSC proliferation and differentiation into oligodendrocytes and neurons, as well as inhibited differentiation into astrocytes, thus promoting remyelination and neuronal repopulation, and reducing astrogliosis; (ii) enhanced anti-inflammatory capacity of BM-NSCs, thus more effectively suppressing CNS inflammation and accelerating remyelination; (iii) the easy accessibility of BM-NSCs provides another advantage over brain-derived NSCs for MS therapy; and (iv) a novel Tet-on system we used enables efficient control of NT-3 expression. Thus, our study provides a novel approach to break the vicious inflammation-demyelination cycle, and could pave the way to an easily accessible and highly effective therapy for CNS inflammatory demyelination.
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Pharmacology, Liaoning University of Traditional Chinese Medicine, Dalian, China.
authors.forename: Jingxian
authors.initials: J
authors.lastname: Yang
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Yaping
authors.initials: Y
authors.lastname: Yan
authors.affiliation: College of Engineering, University of California Berkeley, Berkeley, California, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Xia
authors.affiliation: Department of Pharmacology, Liaoning University of Traditional Chinese Medicine, Dalian, China.
authors.forename: Tingguo
authors.initials: T
authors.lastname: Kang
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Xing
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Bogoljub
authors.initials: B
authors.lastname: Ciric
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Hui
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
authors.forename: Abdolmohamad
authors.initials: A
authors.lastname: Rostami
authors.affiliation: Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Guang-Xian.Zhang@jefferson.edu.
authors.forename: Guang-Xian
authors.initials: GX
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001854:Bone Marrow Cells / Q000166:cytology / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015870:Gene Expression; D017930:Genes, Reporter; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000096:biosynthesis; D056747:Immunomodulation; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016753:Interleukin-10 / Q000096:biosynthesis; D051379:Mice; D009081:Mucolipidoses; D004676:Myelin Basic Protein / Q000096:biosynthesis; D009186:Myelin Sheath / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D020933:Neurotrophin 3 / Q000235:genetics* / Q000378:metabolism; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D004676:Myelin Basic Protein; D020933:Neurotrophin 3; D016753:Interleukin-10