Secondary Release of Exosomes From Astrocytes Contributes to the Increase in Neural Plasticity and Improvement of Functional Recovery After Stroke in Rats Treated With Exosomes Harvested From MicroRNA 133b-Overexpressing Multipotent Mesenchymal Stromal Cells.
We previously demonstrated that multipotent mesenchymal stromal cells (MSCs) that overexpress microRNA 133b (miR-133b) significantly improve functional recovery in rats subjected to middle cerebral artery occlusion (MCAO) compared with naive MSCs and that exosomes generated from naive MSCs mediate the therapeutic benefits of MSC therapy for stroke. Here we investigated whether exosomes isolated from miR-133b-overexpressing MSCs (Ex-miR-133b+) exert amplified therapeutic effects. Rats subjected to 2 h of MCAO were intra-arterially injected with Ex-miR-133b+, exosomes from MSCs infected by blank vector (Ex-Con), or phosphate-buffered saline (PBS) and were sacrificed 28 days after MCAO. Compared with the PBS treatment, both exosome treatment groups exhibited significant improvement of functional recovery. Ex-miR-133b+ treatment significantly increased functional improvement and neurite remodeling/brain plasticity in the ischemic boundary area compared with the Ex-Con treatment. Treatment with Ex-miR-133b+ also significantly increased brain exosome content compared with Ex-Con treatment. To elucidate mechanisms underlying the enhanced therapeutic effects of Ex-miR-133b+, astrocytes cultured under oxygen- and glucose-deprived (OGD) conditions were incubated with exosomes harvested from naive MSCs (Ex-Naive), miR-133b downregulated MSCs (Ex-miR-133b-), and Ex-miR-133b+. Compared with the Ex-Naive treatment, Ex-miR-133b+ significantly increased exosomes released by OGD astrocytes, whereas Ex-miR-133b- significantly decreased the release. Also, exosomes harvested from OGD astrocytes treated with Ex-miR-133b+ significantly increased neurite branching and elongation of cultured cortical embryonic rat neurons compared with the exosomes from OGD astrocytes subjected to Ex-Con. Our data suggest that exosomes harvested from miR-133b-overexpressing MSCs improve neural plasticity and functional recovery after stroke with a contribution from a stimulated secondary release of neurite-promoting exosomes from astrocytes.
Hongqi
H
Xin
Fengjie
F
Wang
Yanfeng
Y
Li
Qing-E
QE
Lu
Wing Lee
WL
Cheung
Yi
Y
Zhang
Zheng Gang
ZG
Zhang
Michael
M
Chopp
D000818:Animals; D001253:Astrocytes / Q000378:metabolism*; D055354:Exosomes / Q000378:metabolism*; D008297:Male; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000378:metabolism* / Q000502:physiology; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009473:Neuronal Plasticity / Q000235:genetics / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D020127:Recovery of Function / Q000502:physiology*; D020521:Stroke / Q000378:metabolism / Q000628:therapy*
D035683:MicroRNAs
J Neurol Sci. 1998 Apr 1;156(2):119-32
9588846
J Cereb Blood Flow Metab. 1992 Jul;12(4):621-8
1618941
Sci Rep. 2015 May 29;5:10721
26024046
J Bioenerg Biomembr. 2004 Aug;36(4):317-21
15377865
Cytometry A. 2010 Jun;77(6):502-14
20235276
J Biol Chem. 2012 Jun 15;287(25):21384-95
22532571
Front Genet. 2012 Apr 20;3:56
22529849
Biochem Biophys Res Commun. 2014 Apr 18;446(4):1165-71
24667602
J Neuropathol Exp Neurol. 1993 Mar;52(2):143-52
8440996
Cold Spring Harb Perspect Biol. 2014 May 01;6(5):a018358
24789822
Brain Pathol. 2016 May;26(3):398-403
26940375
Neural Regen Res. 2013 Aug 15;8(23):2117-25
25206520
J Neurosci Methods. 2003 Sep 30;128(1-2):183-90
12948561
PLoS One. 2010 Feb 03;5(2):e9027
20140248
Front Cell Neurosci. 2013 Oct 30;7:182
24194697
Autophagy. 2009 Feb;5(2):221-3
19029804
Mol Cell Neurosci. 2006 Apr;31(4):642-8
16446100
Prog Neurobiol. 2011 Mar;93(3):313-40
21216273
Stroke. 1995 Nov;26(11):2135-44
7482662
Proc Natl Acad Sci U S A. 2013 Apr 30;110(18):7312-7
23589885
J Extracell Vesicles. 2013 Mar 05;2:null
24009895
Cancer Metastasis Rev. 2013 Dec;32(3-4):449-64
23636348
Br J Haematol. 2003 Nov;123(4):702-11
14616976
Stem Cells. 2013 Dec;31(12):2737-46
23630198
J Pineal Res. 2011 Aug;51(1):124-35
21392095
Physiol Rev. 2003 Jul;83(3):871-932
12843411
J Cell Biochem. 2007 Oct 15;102(3):650-64
17407154
Immunol Lett. 2006 Nov 15;107(2):102-8
17067686
Stem Cell Res Ther. 2016 Apr 16;7(1):55
27084088
Mol Cell Neurosci. 2011 Feb;46(2):409-18
21111824
Stem Cells Transl Med. 2015 Oct;4(10 ):1131-43
26339036
Exp Neurol. 2008 Jun;211(2):588-92
18440506
Bioessays. 2013 Jan;35(1):34-45
23147242
Neurology. 2015 Jul 7;85(1):40-7
26062630
Invest Ophthalmol Vis Sci. 2013 Oct 23;54(10):6944-51
24065814
Ann N Y Acad Sci. 2002 Jun;965:55-67
12105085
J Cereb Blood Flow Metab. 2006 Apr;26(4):556-64
16136056
J Cell Biochem. 2003 Aug 15;89(6):1235-49
12898521
Proteomics Clin Appl. 2007 Nov;1(11):1446-61
21136642
Glia. 2013 Nov;61(11):1795-806
24038411
Biochem Cell Biol. 1995 Sep-Oct;73(9-10):575-92
8714676
J Clin Invest. 2016 Apr 1;126(4):1190-7
27035810
J Cereb Blood Flow Metab. 2013 Nov;33(11):1711-5
23963371
J Cereb Blood Flow Metab. 2011 Nov;31(11):2181-8
21829213
Cell Cycle. 2008 May 1;7(9):1166-72
18418046
J Cell Biol. 1994 May;125(3):573-82
7909812
Front Physiol. 2012 Apr 30;3:119
22557979
J Neurosurg. 2015 Apr;122(4):856-67
25594326
Sci Rep. 2014 Jul 17;4:5715
25030297
Transl Stroke Res. 2013 Dec;4(6):672-84
24323421
Nat Biotechnol. 2011 Apr;29(4):341-5
21423189
J Cell Biol. 1997 Jul 28;138(2):283-90
9230071
Cell Transplant. 2001 Jan-Feb;10(1):31-40
11294470
Physiol Rev. 2014 Oct;94(4):1077-98
25287860
Glia. 2014 Jan;62(1):1-16
24272702
Curr Opin Neurobiol. 2013 Dec;23(6):997-1004
23998929
J Biol Chem. 2012 Dec 14;287(51):43108-15
23129776
J Neurol Sci. 2001 Aug 15;189(1-2):49-57
11535233
J Biol Chem. 2003 May 30;278(22):20083-90
12639953
Cell Death Differ. 2009 Jan;16(1):70-8
19008921
Glia. 2010 Jul;58(9):1074-81
20468049
BMC Cancer. 2012 Sep 24;12:421
22998595
J Biol Chem. 2011 Apr 22;286(16):13805-14
21324893
Exp Cell Res. 2009 May 15;315(9):1584-92
18930046
Am J Pathol. 1995 May;146(5):1045-51
7747798
Circ Res. 2003 Apr 4;92(6):692-9
12609969
Pharm Res. 2015 Jun;32(6):2003-14
25609010
Exp Cell Res. 2004 May 1;295(2):395-406
15093739
Neuroscience. 2008 Mar 27;152(3):646-55
18313231
Elife. 2015 Apr 22;4:e07736
25902403
Cell Death Differ. 2014 Mar;21(3):348-58
24440914
Neurochem Int. 2016 Aug 15;:null
27539657
Acta Neurochir Suppl. 2008;105:79-83
19066087
Biochim Biophys Acta. 2013 Mar;1833(3):503-10
23220125
J Neurosci. 2014 Nov 12;34(46):15482-9
25392515
Nat Rev Neurosci. 2016 Aug;17 (8):467-84
27256553
J Cell Biol. 2004 Apr;165(1):123-33
15078903
Fluids Barriers CNS. 2013 Jul 01;10(1):23
23816186
Front Cell Neurosci. 2013 Dec 10;7:251
24368897
Neurobiol Dis. 2011 Jun;42(3):360-7
21303699
Ther Deliv. 2011 Sep;2(9):1095-9
22833906
Eur J Cancer. 2014 Mar;50(5):1025-34
24462375
J Neurosci. 2011 May 18;31(20):7275-90
21593312
Ment Retard Dev Disabil Res Rev. 2006;12(2):97-104
16807889
J Cereb Blood Flow Metab. 1998 Jan;18(1):2-25
9428302
Adv Drug Deliv Rev. 2013 Mar;65(3):383-90
22921594
Stroke. 2001 Apr;32(4):1005-11
11283404
J Neuropathol Exp Neurol. 1953 Oct;12(4):400-3
13097193
J Cell Biol. 2007 Nov 5;179(3):485-500
17984323
J Vis Exp. 2011 Mar 28;(49):null
21490573
Front Physiol. 2012 May 28;3:145
22654762
J Extracell Vesicles. 2015 Jul 02;4:28239
26142461
J Neurocytol. 1996 Dec;25(12):821-8
9023727
Int J Stroke. 2009 Aug;4(4):250-6
19689750
Stem Cells Int. 2012;2012:652034
22685475
Stem Cells. 2012 Jul;30(7):1556-64
22605481
J Biol Chem. 2007 Aug 31;282(35):25779-89
17591775
J Neurol Sci. 2008 Feb 15;265(1-2):97-101
17610903