title: Inhibition of TROY promotes OPC differentiation and increases therapeutic efficacy of OPC graft for spinal cord injury.
abstract: Endogenous or graft-derived oligodendrocytes promote myelination and aid in the recovery from central nervous system (CNS) injury. Regulatory mechanisms underlying neural myelination and remyelination in response to injury, including spinal cord injury (SCI), are unclear. In the present study, we demonstrated that TROY serves as an important negative regulator of oligodendrocyte development and that TROY inhibition augments the repair potential of oligodendrocyte precursor cell (OPC) graft for SCI. TROY expression was detected by reverse transcriptase-polymerase chain reaction in OPCs as well as in differentiated premature and mature oligodendrocytes of postnatal mice. Pharmacological inhibition or RNAi-induced knockdown of TROY promotes OPC differentiation, whereas overexpression of TROY dampens oligodendrocyte maturation. Further, treatment of cocultures of DRG neurons and OPCs with TROY inhibitors promotes myelination and myelin-sheath-like structures. Mechanically, protein kinase C (PKC) signaling is involved in the regulation of the inhibitory effects of TROY. Moreover, in situ transplantation of OPCs with TROY knockdown leads to notable remyelination and neurological recovery in rats with SCI. Our results indicate that TROY negatively modulates remyelination in the CNS, and thus may be a suitable target for improving the therapeutic efficacy of cell transplantation for CNS injury.
authors.affiliation: 1 Department of Anatomy, School of Basic Medical Sciences, Harbin Medical University , Harbin, China .
authors.forename: Liang
authors.initials: L
authors.lastname: Sun
authors.forename: Shengliang
authors.initials: S
authors.lastname: Liu
authors.forename: Qi
authors.initials: Q
authors.lastname: Sun
authors.forename: Zhuying
authors.initials: Z
authors.lastname: Li
authors.forename: Fengyan
authors.initials: F
authors.lastname: Xu
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hou
authors.forename: Toshihide
authors.initials: T
authors.lastname: Harada
authors.forename: Ming
authors.initials: M
authors.lastname: Chu
authors.forename: Kun
authors.initials: K
authors.lastname: Xu
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Feng
authors.forename: Yongshun
authors.initials: Y
authors.lastname: Duan
authors.forename: Yafang
authors.initials: Y
authors.lastname: Zhang
authors.forename: Shuliang
authors.initials: S
authors.lastname: Wu
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D005260:Female; D055785:Gene Knockdown Techniques; D008810:Mice, Inbred C57BL; D009413:Nerve Fibers, Myelinated / Q000502:physiology; D058953:Neural Stem Cells / Q000502:physiology* / Q000637:transplantation; D009836:Oligodendroglia / Q000502:physiology; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017207:Rats, Sprague-Dawley; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism*; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology; D013119:Spinal Cord Injuries / Q000628:therapy*
chemical_list: D047428:Protein Kinase Inhibitors; D018124:Receptors, Tumor Necrosis Factor; C409471:Tnfrsf19 protein, mouse; D011493:Protein Kinase C
references.citation: J Neurosci Res. 2010 Nov 15;88(15):3233-42
references.pmid: 20882567
references.citation: J Neurosci. 2005 May 11;25(19):4694-705
references.pmid: 15888645
references.citation: Nat Neurosci. 2013 Sep;16(9):1211-1218
references.pmid: 23872599
references.citation: Neuron. 1998 Jul;21(1):63-75
references.pmid: 9697852
references.citation: Ann N Y Acad Sci. 2008 Apr;1126:A1-10
references.pmid: 18584774
references.citation: Nature. 2013 Oct 17;502(7471):327-332
references.pmid: 24107995
references.citation: Proc Natl Acad Sci U S A. 2011 Oct 4;108(40):16825-30
references.pmid: 21949375
references.citation: Crit Care Med. 2012 Feb;40(2):573-9
references.pmid: 22001581
references.citation: Mol Cell. 2005 Aug 5;19(3):309-20
references.pmid: 16061178
references.citation: PLoS One. 2012;7(5):e37955
references.pmid: 22649568
references.citation: Neuropathol Appl Neurobiol. 2007 Feb;33(1):99-107
references.pmid: 17239012
references.citation: J Neurosci. 2006 Jan 4;26(1):328-32
references.pmid: 16399703
references.citation: Nat Neurosci. 2013 Oct;16(10):1370-2
references.pmid: 23995069
references.citation: Exp Neurol. 1996 Jun;139(2):244-56
references.pmid: 8654527
references.citation: Nat Methods. 2011 Sep 25;8(11):957-62
references.pmid: 21946668
references.citation: J Biol Chem. 2000 May 19;275(20):15336-42
references.pmid: 10809768
references.citation: Neuron. 2005 Feb 3;45(3):345-51
references.pmid: 15694321
references.citation: Neuron. 2004 Jul 22;43(2):183-91
references.pmid: 15260955
references.citation: Nat Med. 2007 May;13(5):561-6
references.pmid: 17479102
references.citation: Cell. 2013 Jan 17;152(1-2):248-61
references.pmid: 23332759
references.citation: Glia. 1999 Dec;28(3):244-55
references.pmid: 10559783
references.citation: J Neurosci. 2004 Aug 11;24(32):7140-9
references.pmid: 15306647
references.citation: J Neurotrauma. 2011 Jun;28(6):1089-100
references.pmid: 21309692
references.citation: J Cell Sci. 2004 Mar 15;117(Pt 8):1525-32
references.pmid: 15020679
references.citation: Science. 2011 Sep 16;333(6049):1647-51
references.pmid: 21817014
references.citation: J Neurosurg Spine. 2008 Jan;8(1):58-66
references.pmid: 18173348
references.citation: Nat Rev Neurosci. 2009 Jan;10(1):9-22
references.pmid: 19096367
references.citation: Proc Natl Acad Sci U S A. 2004 Nov 16;101(46):16363-8
references.pmid: 15534218
references.citation: PLoS One. 2012;7(10):e47645
references.pmid: 23091637
references.citation: Cell Stem Cell. 2013 Feb 7;12(2):252-64
references.pmid: 23395447
references.citation: Mol Cancer Res. 2010 Nov;8(11):1558-67
references.pmid: 20881009
references.citation: Int J Biochem Cell Biol. 2008;40(5):1055-64
references.pmid: 18182317
references.citation: Nat Neurosci. 2013 Jun;16(6):668-76
references.pmid: 23624515
references.citation: J Biol Chem. 2002 Nov 22;277(47):45451-7
references.pmid: 12223477
references.citation: Proc Natl Acad Sci U S A. 2010 Mar 2;107(9):4335-40
references.pmid: 20160098
references.citation: Eur J Neurosci. 2006 Jun;23(12):3149-60
references.pmid: 16820005
references.citation: Nat Protoc. 2007;2(5):1044-51
references.pmid: 17546009
references.citation: Nat Rev Neurosci. 2012 Dec;13(12):819-31
references.pmid: 23165259
references.citation: Brain Res. 2006 Sep 19;1110(1):81-94
references.pmid: 16870160
references.citation: Brain. 2009 Feb;132(Pt 2):465-81
references.pmid: 19208690
references.citation: Dev Biol. 2001 Jul 1;235(1):110-20
references.pmid: 11412031
references.citation: Nat Biotechnol. 2013 May;31(5):434-9
references.pmid: 23584610
references.citation: J Neurosci. 2010 May 5;30(18):6422-33
references.pmid: 20445068
references.citation: Proc Natl Acad Sci U S A. 2013 Mar 5;110(10):4075-80
references.pmid: 23431182
references.citation: Neuron. 2005 Feb 3;45(3):353-9
references.pmid: 15694322
references.citation: Science. 2004 Apr 30;304(5671):700-3
references.pmid: 15044753
references.citation: Nat Rev Neurosci. 2006 Dec;7(12):932-41
references.pmid: 17115075
references.citation: Glia. 1998 Feb;22(2):121-9
references.pmid: 9537832
references.citation: J Neurosci. 2011 Mar 30;31(13):5055-66
references.pmid: 21451043
references.citation: Nat Neurosci. 2005 Jun;8(6):745-51
references.pmid: 15895088
references.citation: Brain Res Dev Brain Res. 2003 Jun 12;143(1):105-9
references.pmid: 12763585
references.citation: Dev Biol. 1998 May 1;197(1):54-66
references.pmid: 9578618