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Mol Ther. 2014 Feb;22(2):440-450. doi: 10.1038/mt.2013.241. Epub 2013 Oct 17.

Neurotrophin 3 transduction augments remyelinating and immunomodulatory capacity of neural stem cells.

Author information

1
Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA; Department of Pharmacology, Liaoning University of Traditional Chinese Medicine, Dalian, China.
2
Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
3
College of Engineering, University of California Berkeley, Berkeley, California, USA.
4
Department of Pharmacology, Liaoning University of Traditional Chinese Medicine, Dalian, China.
5
Department of Neurology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA. Electronic address: Guang-Xian.Zhang@jefferson.edu.

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.

PMID:
24247929
PMCID:
PMC3918915
DOI:
10.1038/mt.2013.241
[Indexed for MEDLINE]
Free PMC Article

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