title: MiR-133b promotes neural plasticity and functional recovery after treatment of stroke with multipotent mesenchymal stromal cells in rats via transfer of exosome-enriched extracellular particles.
abstract: To test, in vivo, the hypothesis that exosomes from multipotent mesenchymal stromal cells (MSCs) mediate microRNA 133b (miR-133b) transfer which promotes neurological recovery from stroke, we used knockin and knockdown technologies to upregulate or downregulate the miR-133b level in MSCs (miR-133b(+) MSCs or miR-133b(-) MSCs) and their corresponding exosomes, respectively. Rats were subjected to middle cerebral artery occlusion (MCAo) and were treated with naïve MSCs, miR-133b(+) MSCs, or miR-133b(-) MSC at 1 day after MCAo. Compared with controls, rats receiving naïve MSC treatment significantly improved functional recovery and exhibited increased axonal plasticity and neurite remodeling in the ischemic boundary zone (IBZ) at day 14 after MCAo. The outcomes were significantly enhanced with miR-133b(+) MSC treatment, and were significantly decreased with miR-133b(-) MSC treatment, compared to naïve MSC treatment. The miR-133b level in exosomes collected from the cerebral spinal fluid was significantly increased after miR-133b(+) MSC treatment, and was significantly decreased after miR-133b(-) MSC treatment at day 14 after MCAo, compared to naïve MSC treatment. Tagging exosomes with green fluorescent protein demonstrated that exosomes-enriched extracellular particles were released from MSCs and transferred to adjacent astrocytes and neurons. The expression of selective targets for miR-133b, connective tissue growth factor and ras homolog gene family member A, was significantly decreased in the IBZ after miR-133b(+) MSC treatment, while their expression remained at similar elevated levels after miR-133b(-) MSC treatment, compared to naïve MSC treatment. Collectively, our data suggest that exosomes from MSCs mediate the miR-133b transfer to astrocytes and neurons, which regulate gene expression, subsequently benefit neurite remodeling and functional recovery after stroke.
authors: Department of Neurology, Henry Ford Hospital, Detroit, Michigan, USA.
authors: Hongqi
authors: H
authors: Xin
authors: Yi
authors: Y
authors: Li
authors: Zhongwu
authors: Z
authors: Liu
authors: Xinli
authors: X
authors: Wang
authors: Xia
authors: X
authors: Shang
authors: Yisheng
authors: Y
authors: Cui
authors: Zheng Gang
authors: ZG
authors: Zhang
authors: Michael
authors: M
authors: Chopp
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D002478:Cells, Cultured; D055354:Exosomes / Q000235:genetics* / Q000378:metabolism; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation / Q000379:methods*; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000378:metabolism; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D020521:Stroke / Q000628:therapy*
chemical_list: C549446:MIRN133 microRNA, rat; D035683:MicroRNAs
keywords: Exosomes; Multipotent mesenchymal stromal cells; Neurite remodeling; Stroke; microRNA 133b
references: J Cell Sci. 2011 Feb 1;124(Pt 3):447-58
references: 21242314
references: Exp Cell Res. 2011 May 1;317(8):1192-202
references: 21276792
references: J Cell Physiol. 2007 Feb;210(2):279-89
references: 17096367
references: Neuropsychopharmacology. 2013 Jan;38(1):39-54
references: 22669168
references: J Cereb Blood Flow Metab. 2007 Jan;27(1):6-13
references: 16596121
references: Trends Genet. 2006 Mar;22(3):165-73
references: 16446010
references: Stroke. 2005 Apr;36(4):847-52
references: 15746452
references: Nucleic Acids Res. 2011 May;39(9):3710-23
references: 21247879
references: Eur J Immunol. 2006 Nov;36(11):2875-84
references: 17072917
references: PLoS One. 2011 Feb 23;6(2):e14724
references: 21373187
references: Nature. 2005 Feb 17;433(7027):769-73
references: 15685193
references: Brain Res. 2010 Jun 18;1338:3-13
references: 20380818
references: Physiol Genomics. 2011 May 1;43(10):571-80
references: 21385946
references: Trends Neurosci. 2008 Jan;31(1):20-6
references: 18054394
references: J Cereb Blood Flow Metab. 2010 Jul;30(7):1288-95
references: 20125183
references: Genes Dev. 2003 Apr 15;17(8):991-1008
references: 12672692
references: Adv Drug Deliv Rev. 2013 Mar;65(3):383-90
references: 22921594
references: RNA. 2006 Feb;12(2):187-91
references: 16373485
references: Genome Res. 2009 Jan;19(1):92-105
references: 18955434
references: Biol Direct. 2007 Nov 30;2:35
references: 18053135
references: J Neurocytol. 1996 Dec;25(12):821-8
references: 9023727
references: J Biol Chem. 2011 Jan 7;286(1):787-96
references: 20978131
references: Mol Neurobiol. 2012 Feb;45(1):99-108
references: 22167484
references: Eur J Neurosci. 2000 Jan;12(1):376-80
references: 10651893
references: Cytometry A. 2010 Jun;77(6):502-14
references: 20235276
references: Cell. 2003 Apr 4;113(1):25-36
references: 12679032
references: Curr Pharm Des. 2007;13(24):2470-84
references: 17692015
references: BMC Genomics. 2012 Aug 01;13:357
references: 22849433
references: Neurosci Lett. 2009 Aug 7;459(2):100-4
references: 19406203
references: Stem Cell Res. 2010 May;4(3):214-22
references: 20138817
references: Cell Adh Migr. 2007 Jul-Sep;1(3):156-8
references: 19262134
references: J Neurosurg Spine. 2005 Mar;2(3):319-26
references: 15796357
references: Neuron. 2009 Jan 15;61(1):10-26
references: 19146809
references: Genome Biol. 2007;8(8):R173
references: 17711588
references: Cereb Cortex. 2004 Nov;14(11):1276-86
references: 15166101
references: Blood. 2002 May 15;99(10):3838-43
references: 11986244
references: Dev Biol. 2006 Jan 1;289(1):3-16
references: 16325172
references: Glia. 2008 Nov 15;56(15):1691-709
references: 18618667
references: Eur J Neurosci. 2011 May;33(9):1587-97
references: 21447094
references: J Clin Neurosci. 2009 Jan;16(1):12-20
references: 19017556
references: Am J Pathol. 1995 May;146(5):1045-51
references: 7747798
references: Oncogene. 2012 Sep 6;31(36):4067-75
references: 22179829
references: Cell Mol Life Sci. 2012 Jan;69(1):89-102
references: 21833581
references: J Neurosci. 2006 May 24;26(21):5727-32
references: 16723529
references: Restor Neurol Neurosci. 2008;26(2-3):197-214
references: 18820411
references: Neuromolecular Med. 2009;11(3):162-72
references: 19536656
references: Biochem Pharmacol. 2011 May 15;81(10):1171-82
references: 21371441
references: Cell Transplant. 2007;16(2):171-81
references: 17474298
references: Commun Integr Biol. 2010 Sep;3(5):447-50
references: 21057637
references: Nat Methods. 2006 Jan;3(1):27-9
references: 16369549
references: J Endocrinol. 2005 Dec;187(3):327-32
references: 16423811
references: Nature. 2005 Aug 18;436(7053):1020-1024
references: 16107849
references: Biotechnol Adv. 2013 Sep-Oct;31(5):543-51
references: 22959595
references: Int J Stroke. 2009 Aug;4(4):250-6
references: 19689750
references: Proc Natl Acad Sci U S A. 2005 Aug 2;102(31):10898-903
references: 16040801
references: J Neurosci Res. 2003 Sep 15;73(6):778-86
references: 12949903
references: J Neurosci. 2004 Jul 7;24(27):6209-17
references: 15240813
references: Science. 2004 Jan 2;303(5654):83-6
references: 14657504
references: Stroke. 2011 Mar;42(3):740-4
references: 21307396
references: J Vis Exp. 2011 Mar 28;(49):
references: 21490573
references: J Mol Neurosci. 2008 Jul;35(3):331-7
references: 18452032
references: Glia. 2008 Dec;56(16):1747-54
references: 18618668
references: Biochim Biophys Acta. 2008 Aug;1779(8):471-8
references: 18194678
references: J Transl Med. 2011 Apr 25;9:47
references: 21513579
references: Behav Neurosci. 1984 Jun;98(3):518-40
references: 6539617
references: Adv Drug Deliv Rev. 2013 Mar;65(3):336-41
references: 22780955
references: PLoS One. 2010 Dec 17;5(12):e15353
references: 21179422
references: Stroke. 2001 Apr;32(4):1005-11
references: 11283404
references: Circ Res. 2009 Jan 30;104(2):170-8, 6p following 178
references: 19096030
references: Nat Cell Biol. 2007 Jun;9(6):654-9
references: 17486113
references: Proc Natl Acad Sci U S A. 2010 Apr 6;107(14):6328-33
references: 20304794
references: Stem Cells. 2012 Jul;30(7):1556-64
references: 22605481
references: Front Physiol. 2012 Jun 27;3:228
references: 22754538
references: J Neurotrauma. 2001 Apr;18(4):377-88
references: 11336439
references: Exp Neurol. 2006 Apr;198(2):313-25
references: 16455080
references: PLoS One. 2011;6(5):e20399
references: 21637820
references: Cell. 2005 Jan 14;120(1):15-20
references: 15652477
references: J Immunol. 2008 Mar 1;180(5):3081-90
references: 18292531
references: Exp Cell Res. 2004 May 1;295(2):395-406
references: 15093739
references: Cold Spring Harb Perspect Biol. 2010 Feb;2(2):a001818
references: 20182621
references: Neuropathol Appl Neurobiol. 2000 Oct;26(5):434-40
references: 11054183
references: Stroke. 2010 Dec;41(12):2979-81
references: 20966418
references: Stem Cells. 2008 Feb;26(2):356-63
references: 17991914
references: J Alzheimers Dis. 2010;19(1):37-56
references: 20061625
references: Exp Cell Res. 2009 May 15;315(9):1584-92
references: 18930046
references: Science. 2005 May 6;308(5723):833-8
references: 15774722
references: J Cell Biochem. 2003 Aug 15;89(6):1235-49
references: 12898521
references: Br J Haematol. 2003 Nov;123(4):702-11
references: 14616976
references: Cell. 2004 Jan 23;116(2):281-97
references: 14744438
references: J Neurosci Methods. 2003 Sep 30;128(1-2):183-90
references: 12948561
references: J Neural Transm (Vienna). 2010 Jan;117(1):1-4
references: 19680595
references: Cancer Res. 2010 Nov 1;70(21):8259-63
references: 20841486
references: J Cell Biochem. 2006 Aug 1;98(5):1076-84
references: 16619257
references: J Proteomics. 2010 Sep 10;73(10):1907-20
references: 20601276
references: Stroke. 2003 Jul;34(7):1790-5
references: 12805500
references: Neuron. 2000 Feb;25(2):307-16
references: 10719887
references: Proc Natl Acad Sci U S A. 1988 Mar;85(6):1998-2002
references: 2450354
references: Circ Res. 2003 Apr 4;92(6):692-9
references: 12609969
references: Glia. 2005 Feb;49(3):407-17
references: 15540231
references: RNA. 2008 Mar;14(3):432-44
references: 18230762
references: J Neurosci. 2011 May 18;31(20):7275-90
references: 21593312