Mesenchymal Stem Cells Ameliorate Cuprizone-Induced Demyelination by Targeting Oxidative Stress and Mitochondrial Dysfunction.
Animals
Cuprizone
/ pharmacology
Demyelinating Diseases
/ drug therapy
Disease Models, Animal
Humans
Male
Mesenchymal Stem Cells
/ metabolism
Mice, Inbred C57BL
Mitochondria
/ drug effects
Multiple Sclerosis
/ metabolism
Myelin Sheath
/ drug effects
Oligodendroglia
/ drug effects
Oxidative Stress
/ drug effects
Remyelination
/ drug effects
Cuprizone
Mesenchymal stem cells
Mitochondria
Multiple sclerosis
Myelination
Oxidative stress
Journal
Cellular and molecular neurobiology
ISSN: 1573-6830
Titre abrégé: Cell Mol Neurobiol
Pays: United States
ID NLM: 8200709
Informations de publication
Date de publication:
Oct 2021
Oct 2021
Historique:
received:
31
03
2020
accepted:
22
06
2020
pubmed:
1
7
2020
medline:
14
1
2022
entrez:
29
6
2020
Statut:
ppublish
Résumé
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system. The main causes of MS disease progression, demyelination, and tissue damage are oxidative stress and mitochondrial dysfunction. Hence, the latter are considered as important therapeutic targets. Recent studies have demonstrated that mesenchymal stem cells (MSCs) possess antioxidative properties and are able to target mitochondrial dysfunction. Therefore, we investigated the effect of transplanting Wharton's jelly-derived MSCs in a demyelination mouse model of MS in which mice were fed cuprizone (CPZ) for 12 weeks. CPZ is a copper chelator that impairs the activity of cytochrome oxidase, decreases oxidative phosphorylation, and produces degenerative changes in oligodendrocytes, leading to toxic demyelination similar to those found in MS patients. Results showed that MSCs caused a significant increase in the percentage of myelinated areas and in the number of myelinated fibers in the corpus callosum of the CPZ + MSC group, compared to the CPZ group, as assessed by Luxol fast blue staining and transmission electron microscopy. In addition, transplantation of MSCs significantly increased the number of oligodendrocytes while decreasing astrogliosis and microgliosis in the corpus callosum of the CPZ + MSC group, evaluated by immunofluorescence. Moreover, the mechanism by which MSCs exert these physiological effects was found to be through abolishing the effect of CPZ on oxidative stress markers and mitochondrial dysfunction. Indeed, malondialdehyde significantly decreased while glutathione and superoxide dismutase significantly increased in CPZ + MSC mice group, in comparison witth the CPZ group alone. Furthermore, cell therapy with MSC transplantation increased the expression levels of mitochondrial biogenesis transcripts PGC1α, NRF1, MFN2, and TFAM. In summary, these results demonstrate that MSCs may attenuate MS by promoting an antioxidant response, reducing oxidative stress, and improving mitochondrial homeostasis.
Identifiants
pubmed: 32594382
doi: 10.1007/s10571-020-00910-6
pii: 10.1007/s10571-020-00910-6
doi:
Substances chimiques
Cuprizone
5N16U7E0AO
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1467-1481Subventions
Organisme : Tehran University of Medical Sciences and Health Services
ID : 97-03-30-39671
Organisme : Université Libanaise
ID : 2017-25652
Informations de copyright
© 2020. Springer Science+Business Media, LLC, part of Springer Nature.
Références
Abrams MB, Dominguez C, Pernold K, Reger R, Wiesenfeld-Hallin Z, Olson L, Prockop D (2009) Multipotent mesenchymal stromal cells attenuate chronic inflammation and injury-induced sensitivity to mechanical stimuli in experimental spinal cord injury. Restor Neurol Neurosci 27:307–321
pubmed: 19738324
Ayatollahi M, Hesami Z, Jamshidzadeh A, Gramizadeh B (2014) Antioxidant effects of bone marrow mesenchymal stem cell against carbon tetrachloride-induced oxidative damage in rat livers. Int J Organ Transplant Med 5:166
pubmed: 25426285
pmcid: 4243048
Barati S, Kashani IR, Tahmasebi F, Mehrabi S, Joghataei MT (2019) Effect of mesenchymal stem cells on glial cells population in cuprizone induced demyelination model. Neuropeptides 75:75–84
pubmed: 31030907
doi: 10.1016/j.npep.2019.04.001
Brooks C, Cho S-G, Wang C-Y, Yang T, Dong Z (2010) Fragmented mitochondria are sensitized to bax insertion and activation during apoptosis. Am J Physiol Cell Physiol 300:C447–C455
pubmed: 21160028
pmcid: 3063970
doi: 10.1152/ajpcell.00402.2010
Castro-Manrreza ME, Montesinos JJ (2015) Immunoregulation by mesenchymal stem cells: biological aspects and clinical applications. J Immunol Res. https://doi.org/10.1155/2015/394917
doi: 10.1155/2015/394917
pubmed: 25961059
pmcid: 4417567
Chi H, Guan Y, Li F, Chen Z (2019) The effect of human umbilical cord mesenchymal stromal cells in protection of dopaminergic neurons from apoptosis by reducing oxidative stress in the early stage of a 6-OHDA-induced Parkinson’s disease model. Cell Transplant 28:87S
pubmed: 31775521
pmcid: 7016462
doi: 10.1177/0963689719891134
Clarner T et al (2012) Myelin debris regulates inflammatory responses in an experimental demyelination animal model and multiple sclerosis lesions. Glia 60:1468–1480
pubmed: 22689449
doi: 10.1002/glia.22367
Cruz-Martinez P et al (2016) Intraventricular injections of mesenchymal stem cells activate endogenous functional remyelination in a chronic demyelinating murine model. Cell Death Dis 7:e2223
pubmed: 27171265
pmcid: 4917663
doi: 10.1038/cddis.2016.130
da Costa GF et al (2017) Antioxidant properties of mesenchymal stem cells against oxidative stress in a murine model of colitis. Biotechnol Lett 39:613–622
doi: 10.1007/s10529-016-2272-3
Dantuma E, Merchant S, Sugaya K (2010) Stem cells for the treatment of neurodegenerative diseases. Stem Cell Res Ther 1:37
pubmed: 21144012
pmcid: 3025439
doi: 10.1186/scrt37
Ekstrand MI et al (2004) Mitochondrial transcription factor A regulates mtDNA copy number in mammals. Hum Mol Genet 13:935–944
pubmed: 15016765
doi: 10.1093/hmg/ddh109
Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. New Engl J Med 354:942–955
pubmed: 16510748
doi: 10.1056/NEJMra052130
Gao F, Koenitzer JR, Tobolewski JM, Jiang D, Liang J, Noble PW, Oury TD (2008) Extracellular superoxide dismutase inhibits inflammation by preventing oxidative fragmentation of hyaluronan. J Biol Chem 283:6058–6066
pubmed: 18165226
doi: 10.1074/jbc.M709273200
Geng X et al (2017) Biological membrane-packed mesenchymal stem cells treat acute kidney disease by ameliorating mitochondrial-related apoptosis. Sci Rep 7:41136
pubmed: 28117405
pmcid: 5259718
doi: 10.1038/srep41136
Ghaiad HR, Nooh MM, El-Sawalhi MM, Shaheen AA (2017) Resveratrol promotes remyelination in cuprizone model of multiple sclerosis: biochemical and histological study. Mol Neurobiol 54:3219–3229
pubmed: 27067589
doi: 10.1007/s12035-016-9891-5
Goldberg JL, Barres BA (2000) The relationship between neuronal survival and regeneration. Annu Rev Neurosci 23:579–612
pubmed: 10845076
doi: 10.1146/annurev.neuro.23.1.579
Gu D, Zou X, Ju G, Zhang G, Bao E, Zhu Y (2016) Mesenchymal stromal cells derived extracellular vesicles ameliorate acute renal ischemia reperfusion injury by inhibition of mitochondrial fission through miR-30. Stem Cells Int. https://doi.org/10.1155/2016/2093940
doi: 10.1155/2016/2093940
pubmed: 27799943
pmcid: 5069372
Hedayatpour A et al (2013) Promotion of remyelination by adipose mesenchymal stem cell transplantation in a cuprizone model of multiple sclerosis. Cell J (Yakhteh) 15:142
Joyce N, Annett G, Wirthlin L, Olson S, Bauer G, Nolta JA (2010) Mesenchymal stem cells for the treatment of neurodegenerative disease. Regener Med 5:933–946
doi: 10.2217/rme.10.72
Kang C, Ji LL (2013) Role of PGC-1α in muscle function and aging. J Sport Health Sci 2:81–86
doi: 10.1016/j.jshs.2013.03.005
Kang Z et al (2012) IL-17-induced Act1-mediated signaling is critical for cuprizone-induced demyelination. J Neurosci 32:8284–8292
pubmed: 22699909
pmcid: 3412399
doi: 10.1523/JNEUROSCI.0841-12.2012
Kaplan DR, Miller FD (2000) Neurotrophin signal transduction in the nervous system. Curr Opin Neurobiol 10:381–391
pubmed: 10851172
doi: 10.1016/S0959-4388(00)00092-1
Karussis D et al (2010) Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 67:1187–1194
pubmed: 20937945
pmcid: 3036569
doi: 10.1001/archneurol.2010.248
Kashani IR et al (2014) Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis. Exp Brain Res 232:2835–2846
pubmed: 24798398
doi: 10.1007/s00221-014-3946-5
Kemp K, Gray E, Mallam E, Scolding N, Wilkins A (2010a) Inflammatory cytokine induced regulation of superoxide dismutase 3 expression by human mesenchymal stem cells. Stem Cell Rev Rep 6:548–559
pubmed: 20683679
doi: 10.1007/s12015-010-9178-6
Kemp K, Hares K, Mallam E, Heesom KJ, Scolding N, Wilkins A (2010b) Mesenchymal stem cell-secreted superoxide dismutase promotes cerebellar neuronal survival. J Neurochem 114:1569–1580
pubmed: 20028455
doi: 10.1111/j.1471-4159.2009.06553.x
Khaldoyanidi S (2008) Directing stem cell homing. Cell Stem Cell 2:198–200
pubmed: 18371444
doi: 10.1016/j.stem.2008.02.012
Kieseier BC, Stüve O (2011) A critical appraisal of treatment decisions in multiple sclerosis—old versus new. Nat Rev Neurol 7:255
pubmed: 21467994
doi: 10.1038/nrneurol.2011.41
Kim J-H et al (2008) The non-provitamin A carotenoid, lutein, inhibits NF-κB-dependent gene expression through redox-based regulation of the phosphatidylinositol 3-kinase/PTEN/Akt and NF-κB-inducing kinase pathways: role of H2O2 in NF-κB activation. Free Radic Biol Med 45:885–896
pubmed: 18620044
doi: 10.1016/j.freeradbiomed.2008.06.019
Kim YJ et al (2009) Neuroprotective effects of human mesenchymal stem cells on dopaminergic neurons through anti-inflammatory action. Glia 57:13–23
pubmed: 18661552
doi: 10.1002/glia.20731
Largani SHH et al (2019) Oligoprotective effect of metformin through the AMPK-dependent on restoration of mitochondrial hemostasis in the cuprizone-induced multiple sclerosis model. J Mol Histol 50:263–271
pubmed: 31016544
doi: 10.1007/s10735-019-09824-0
Laurila JP, Laatikainen LE, Castellone MD, Laukkanen MO (2009) SOD3 reduces inflammatory cell migration by regulating adhesion molecule and cytokine expression. PLoS ONE 4:e5786
pubmed: 19495415
pmcid: 2686160
doi: 10.1371/journal.pone.0005786
Liesa M et al (2008) Mitochondrial fusion is increased by the nuclear coactivator PGC-1β. PLoS ONE 3:e3613
pubmed: 18974884
pmcid: 2570954
doi: 10.1371/journal.pone.0003613
Lu F, Selak M, O’Connor J, Croul S, Lorenzana C, Butunoi C, Kalman B (2000) Oxidative damage to mitochondrial DNA and activity of mitochondrial enzymes in chronic active lesions of multiple sclerosis. J Neurol Sci 177:95–103
pubmed: 10980305
doi: 10.1016/S0022-510X(00)00343-9
Mao P, Reddy PH (2010) Is multiple sclerosis a mitochondrial disease? Biochim Biophys Acta (BBA) Mol Basis Dis 1802:66–79
doi: 10.1016/j.bbadis.2009.07.002
McManus MJ, Murphy MP, Franklin JL (2011) The mitochondria-targeted antioxidant MitoQ prevents loss of spatial memory retention and early neuropathology in a transgenic mouse model of Alzheimer's disease. J Neurosci 31:15703–15715
pubmed: 22049413
pmcid: 3334845
doi: 10.1523/JNEUROSCI.0552-11.2011
Nahirnyj A, Livne-Bar I, Guo X, Sivak JM (2013) ROS detoxification and proinflammatory cytokines are linked by p38 MAPK signaling in a model of mature astrocyte activation. PLoS ONE 8:e83049
pubmed: 24376630
pmcid: 3871647
doi: 10.1371/journal.pone.0083049
Nessler J et al (2013) Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination. PLoS ONE 8:e69795
pubmed: 23922802
pmcid: 3724887
doi: 10.1371/journal.pone.0069795
Ohno N et al (2014) Mitochondrial immobilization mediated by syntaphilin facilitates survival of demyelinated axons. Proc Natl Acad Sci 111:9953–9958
pubmed: 24958879
pmcid: 4103317
doi: 10.1073/pnas.1401155111
Ortiz GG et al (2016) Multiple sclerosis and its relationship with oxidative stress, glutathione redox system, ATPase system, and membrane fluidity. Trending Top Mult Scler 5:150–166
Ozdemir D et al (2005) Effect of melatonin on brain oxidative damage induced by traumatic brain injury in immature rats. Physiol Res 54:631
pubmed: 15720160
Peng X et al (2013) Human umbilical cord mesenchymal stem cells attenuate cisplatin-induced acute and chronic renal injury. Exp Biol Med 238:960–970
doi: 10.1177/1477153513497176
Perico L et al (2017a) Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun 8:983
pubmed: 29042548
pmcid: 5754365
doi: 10.1038/s41467-017-00937-2
Perico L et al (2017b) Human mesenchymal stromal cells transplanted into mice stimulate renal tubular cells and enhance mitochondrial function. Nat Commun 8:1–17
doi: 10.1038/s41467-017-00937-2
Praet J, Guglielmetti C, Berneman Z, Van der Linden A, Ponsaerts P (2014) Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 47:485–505
pubmed: 25445182
doi: 10.1016/j.neubiorev.2014.10.004
pmcid: 25445182
Rad F, Ghorbani M, Roushandeh AM, Roudkenar MH (2019) Mesenchymal stem cell-based therapy for autoimmune diseases: emerging roles of extracellular vesicles. Mol Biol Rep 46:1533–1549
pubmed: 30623280
doi: 10.1007/s11033-019-04588-y
Rivera FJ, Aigner L (2012) Adult mesenchymal stem cell therapy for myelin repair in multiple sclerosis. Biol Res 45:257–268
pubmed: 23283435
doi: 10.4067/S0716-97602012000300007
pmcid: 23283435
Rosset P, Deschaseaux F, Layrolle P (2014) Cell therapy for bone repair. Orthop Traumatol Surg Res 100:S107–S112
pubmed: 24411717
doi: 10.1016/j.otsr.2013.11.010
Sághy É et al (2016) TRPA1 deficiency is protective in cuprizone-induced demyelination—a new target against oligodendrocyte apoptosis. Glia 64:2166–2180
pubmed: 27568827
doi: 10.1002/glia.23051
pmcid: 27568827
Sanadgol N, Golab F, Mostafaie A, Mehdizadeh M, Abdollahi M, Sharifzadeh M, Ravan H (2016) Ellagic acid ameliorates cuprizone-induced acute CNS inflammation via restriction of microgliosis and down-regulation of CCL2 and CCL3 pro-inflammatory chemokines. Cell Mol Biol 62:24–30
pubmed: 27894396
Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim et Biophys Acta (BBA) Mol Cell Res 1813:1269–1278
doi: 10.1016/j.bbamcr.2010.09.019
Shalaby SM et al (2014) Mesenchymal stromal cell injection protects against oxidative stress in Escherichia coli–induced acute lung injury in mice. Cytotherapy 16:764–775
pubmed: 24525173
doi: 10.1016/j.jcyt.2013.12.006
Smirnova L, Krotenko N, Grishko E, Krotenko N, Alifirova V, Ivanova S (2011) The state of the antioxidant system during therapy of patients with multiple sclerosis. Biochem (Moscow) Suppl Ser B 5:76
doi: 10.1134/S1990750811010136
Sözmen EG, Carmichael ST (2014) White matter repair in subcortical stroke. In: Baltan S, Carmichael S, Matute C, Xi G, Zhang J (eds) White matter Injury in stroke and CNS disease. Springer, New York, pp 257–270
doi: 10.1007/978-1-4614-9123-1_12
Sun T et al (2015) Bone marrow-derived mesenchymal stem cell transplantation ameliorates oxidative stress and restores intestinal mucosal permeability in chemically induced colitis in mice. Am J Transl Res 7:891
pubmed: 26175850
pmcid: 4494140
Tejedor LS (2015) Central nervous system regeneration approach in the toxic cuprizone model of de-and remyelination: application of mesenchymal stem cells. Tierärztl. Hochsch
Wu H, Kanatous SB, Thurmond FA, Gallardo T, Isotani E, Bassel-Duby R, Williams RS (2002) Regulation of mitochondrial biogenesis in skeletal muscle by CaMK. Science 296:349–352
pubmed: 11951046
doi: 10.1126/science.1071163
Yang J et al (2015) Extracellular vesicles derived from bone marrow mesenchymal stem cells protect against experimental colitis via attenuating colon inflammation, oxidative stress and apoptosis. PLoS ONE 10:e0140551
pubmed: 26469068
pmcid: 4607447
doi: 10.1371/journal.pone.0140551
Yeung AWK et al (2020) Reactive oxygen species (ROS) and their impact in neurodegenerative diseases: literature landscape analysis. Antioxid Redox Signal. https://doi.org/10.1089/ars.2019.7952
doi: 10.1089/ars.2019.7952
pubmed: 32030995
Yu B, Zhang X, Li X (2014) Exosomes derived from mesenchymal stem cells. Int J Mol Sci 15:4142–4157
pubmed: 24608926
pmcid: 3975389
doi: 10.3390/ijms15034142
Yuan Y et al (2016) Mesenchymal stem cell-conditioned media ameliorate diabetic endothelial dysfunction by improving mitochondrial bioenergetics via the Sirt1/AMPK/PGC-1α pathway. Clin Sci 130:2181–2198
doi: 10.1042/CS20160235
Zendedel A et al (2016) Regulatory effect of triiodothyronine on brain myelination and astrogliosis after cuprizone-induced demyelination in mice. Metab Brain Dis 31:425–433
pubmed: 26725831
doi: 10.1007/s11011-015-9781-y