Generic placeholder image

Current Stem Cell Research & Therapy

Editor-in-Chief

ISSN (Print): 1574-888X
ISSN (Online): 2212-3946

Research Article

Anti-inflammatory Effects of Umbilical Cord Mesenchymal Stem Cell and Autologous Conditioned Serum on Oligodendrocyte, Astrocyte, and Microglial Specific Gene in Cuprizone Animal Model

Author(s): Omid Alavi, Aliakbar Alizadeh*, Farzaneh Dehghani*, Hamed Alipour and Nader Tanideh

Volume 19, Issue 1, 2024

Published on: 11 April, 2023

Page: [71 - 82] Pages: 12

DOI: 10.2174/1574888X18666230228102731

Price: $65

Abstract

Background: Inflammation, myelin loss, astrocytosis, and microgliosis are pathological signs of the autoimmune and demyelinating disease known as multiple sclerosis (MS). Axonal and neuronal degenerations have basic molecular pathways. The remyelination process can be influenced by the secretome of mesenchymal stem cells due to their capacity for immunomodulation, differentiation, and neuroprotection. Microglial cells are divided into two subgroups: M1 and M2 phenotypes. A crucial component of the microglial function is the colony stimulating factor 1 receptor (CSF1R). We aimed to evaluate the immunomodulating effects of secretome and conditioned serum on the microglial phenotypes and improvement of demyelination in a cuprizone model of MS.

Methods: The study used 48 male C57BL/6 mice, which were randomly distributed into 6 subgroups (n = 8), i.e., control, cuprizone, MSC (confluency 40% and 80%) secretome group, and blood derived conditioned serum (autologous and humanized). The animals were fed with 0.2% cuprizone diet for 12 weeks. Supplements were injected into the lateral tail vein using a 27-gauge needle every 3 days 500 μl per injection.

Results: At 14 days after transplantation, animals from each group were sacrificed and analyzed by Real time PCR. The results showed that the administration of MSC secretome can efficiently reduce expression of pro-inflammatory cytokines (IL-1, IL6 and TNF-α) in the corpus callosum; also, conditioned serum downregulated IL-1. Moreover, the oligodendrocyte-specific gene was upregulated by secretome and conditioned serum treatment. Also, the expression of microglial- specific gene was reduced after treatment.

Conclusion: These findings demonstrated that the secretome isolated from MSCs used as a therapy decreased and increased the M1 and M2 levels, respectively, to control neuroinflammation in CPZ mice. In conclusion, the current study showed the viability of devising a method to prepare suitable MSCs and secreted factor to cure neurodegenerative diseases, as well as the capability of regulating MSC secretome patterns by manipulating the cell density.

Graphical Abstract

[1]
Martínez-Pinilla E, Rubio-Sardón N, Villar-Conde S, et al. Cuprizone-induced neurotoxicity in human neural cell lines is mediated by a reversible mitochondrial dysfunction: Relevance for demyelination models. Brain Sci 2021; 11(2): 272.
[http://dx.doi.org/10.3390/brainsci11020272] [PMID: 33671675]
[2]
Shiri E, Pasbakhsh P, Borhani-Haghighi M, et al. Mesenchymal stem cells ameliorate cuprizone-induced demyelination by targeting oxidative stress and mitochondrial dysfunction. Cell Mol Neurobiol 2021; 41(7): 1467-81.
[http://dx.doi.org/10.1007/s10571-020-00910-6] [PMID: 32594382]
[3]
Nessler J, Bénardais K, Gudi V, et al. Effects of murine and human bone marrow-derived mesenchymal stem cells on cuprizone induced demyelination. PLoS One 2013; 8(7): e69795.
[http://dx.doi.org/10.1371/journal.pone.0069795] [PMID: 23922802]
[4]
Rajan TS, Diomede F, Bramanti P, Trubiani O, Mazzon E. Conditioned medium from human gingival mesenchymal stem cells protects motor-neuron-like NSC-34 cells against scratch-injury-induced cell death. Int J Immunopathol Pharmacol 2017; 30(4): 383-94.
[http://dx.doi.org/10.1177/0394632017740976] [PMID: 29140156]
[5]
Martínez-Pinilla E, Rubio-Sardón N, Peláez R, et al. Neuroprotective effect of apolipoprotein d in cuprizone-induced cell line models: A potential therapeutic approach for multiple sclerosis and demyelinating diseases. Int J Mol Sci 2021; 22(3): 1260.
[http://dx.doi.org/10.3390/ijms22031260] [PMID: 33514021]
[6]
Barati S, Kashani IR, Tahmasebi F. The effects of mesenchymal stem cells transplantation on A1 neurotoxic reactive astrocyte and demyelination in the cuprizone model. J Mol Histol 2022; 53(2): 333-46.
[http://dx.doi.org/10.1007/s10735-021-10046-6] [PMID: 35031895]
[7]
Procaccini C, De Rosa V, Pucino V, Formisano L, Matarese G. Animal models of multiple sclerosis. Eur J Pharmacol 2015; 759: 182-91.
[http://dx.doi.org/10.1016/j.ejphar.2015.03.042] [PMID: 25823807]
[8]
Praet J, Guglielmetti C, Berneman Z, Van der Linden A, Ponsaerts P. Cellular and molecular neuropathology of the cuprizone mouse model: Clinical relevance for multiple sclerosis. Neurosci Biobehav Rev 2014; 47: 485-505.
[http://dx.doi.org/10.1016/j.neubiorev.2014.10.004] [PMID: 25445182]
[9]
Messori L, Casini A, Gabbiani C, Sorace L, Muniz-Miranda M, Zatta P. Unravelling the chemical nature of copper cuprizone. Dalton Trans 2007; (21): 2112-4.
[http://dx.doi.org/10.1039/b701896g] [PMID: 17514330]
[10]
Smirnova LP, et al. The state of the antioxidant system during therapy of patients with multiple sclerosis Biochem Moscow Suppl Ser B5, 76-80 (2011).
[11]
Yeung AWK, Tzvetkov NT, Georgieva MG, et al. Reactive oxygen species and their impact in neurodegenerative diseases: Literature landscape analysis. Antioxid Redox Signal 2021; 34(5): 402-20.
[http://dx.doi.org/10.1089/ars.2019.7952] [PMID: 32030995]
[12]
Barati S, Ragerdi Kashani I, Moradi F, et al. Mesenchymal stem cell mediated effects on microglial phenotype in cuprizone‐induced demyelination model. J Cell Biochem 2019; 120(8): 13952-64.
[http://dx.doi.org/10.1002/jcb.28670] [PMID: 30963634]
[13]
Poniatowski ŁA, Wojdasiewicz P, Krawczyk M, et al. Analysis of the role of CX3CL1 (Fractalkine) and Its receptor CX3CR1 in traumatic brain and spinal cord injury: insight into recent advances in actions of neurochemokine agents. Mol Neurobiol 2017; 54(3): 2167-88.
[http://dx.doi.org/10.1007/s12035-016-9787-4] [PMID: 26927660]
[14]
Kim KW, Vallon-Eberhard A, Zigmond E, et al. In vivo structure/function and expression analysis of the CX3C chemokine fractalkine. Blood 2011; 118(22): e156-67.
[http://dx.doi.org/10.1182/blood-2011-04-348946] [PMID: 21951685]
[15]
Gibson EM, Geraghty AC, Monje M. Bad wrap: Myelin and myelin plasticity in health and disease. Dev Neurobiol 2018; 78(2): 123-35.
[http://dx.doi.org/10.1002/dneu.22541] [PMID: 28986960]
[16]
Tahmasebi F, Barati S, Kashani IR. Effect of CSF1R inhibitor on glial cells population and remyelination in the cuprizone model. Neuropeptides 2021; 89: 102179.
[http://dx.doi.org/10.1016/j.npep.2021.102179] [PMID: 34274854]
[17]
Haider L, Fischer MT, Frischer JM, et al. Oxidative damage in multiple sclerosis lesions. Brain 2011; 134(7): 1914-24.
[http://dx.doi.org/10.1093/brain/awr128] [PMID: 21653539]
[18]
Wang H, Xu L, Lai C, et al. Region-specific distribution of Olig2-expressing astrocytes in adult mouse brain and spinal cord. Mol Brain 2021; 14(1): 36.
[http://dx.doi.org/10.1186/s13041-021-00747-0] [PMID: 33618751]
[19]
Tatsumi K, Isonishi A, Yamasaki M, et al. Olig2-lineage astrocytes: A distinct subtype of astrocytes that differs from GFAP astrocytes. Front Neuroanat 2018; 12: 8.
[http://dx.doi.org/10.3389/fnana.2018.00008] [PMID: 29497365]
[20]
Miller SJ, Philips T, Kim N, et al. Molecularly defined cortical astroglia subpopulation modulates neurons via secretion of Norrin. Nat Neurosci 2019; 22(5): 741-52.
[http://dx.doi.org/10.1038/s41593-019-0366-7] [PMID: 30936556]
[21]
Jiang P, Chen C, Wang R, et al. hESC-derived Olig2+ progenitors generate a subtype of astroglia with protective effects against ischaemic brain injury. Nat Commun 2013; 4(1): 2196.
[http://dx.doi.org/10.1038/ncomms3196] [PMID: 23880652]
[22]
Tatsumi K, Kinugawa K, Isonishi A, et al. Olig2-astrocytes express neutral amino acid transporter SLC7A10 (Asc-1) in the adult brain. Mol Brain 2021; 14(1): 163.
[http://dx.doi.org/10.1186/s13041-021-00874-8] [PMID: 34749773]
[23]
Kim DS, Lee MW, Lee TH, Sung KW, Koo HH, Yoo KH. Cell culture density affects the stemness gene expression of adipose tissue-derived mesenchymal stem cells. Biomed Rep 2017; 6(3): 300-6.
[http://dx.doi.org/10.3892/br.2017.845] [PMID: 28451390]
[24]
Paré B, Deschênes LT, Pouliot R, Dupré N, Gros-Louis F. An optimized approach to recover secreted proteins from fibroblast conditioned-media for secretomic analysis. Front Cell Neurosci 2016; 10: 70.
[http://dx.doi.org/10.3389/fncel.2016.00070] [PMID: 27064649]
[25]
Infante A, Rodríguez CI. Secretome analysis of in vitro aged human mesenchymal stem cells reveals IGFBP7 as a putative factor for promoting osteogenesis. Sci Rep 2018; 8(1): 4632.
[http://dx.doi.org/10.1038/s41598-018-22855-z] [PMID: 29545581]
[26]
Park SR, Kim JW, Jun HS, Roh JY, Lee HY, Hong IS. Stem cell secretome and its effect on cellular mechanisms relevant to wound healing. Mol Ther 2018; 26(2): 606-17.
[http://dx.doi.org/10.1016/j.ymthe.2017.09.023] [PMID: 29066165]
[27]
Teixeira FG, Carvalho MM, Sousa N, Salgado AJ. Mesenchymal stem cells secretome: A new paradigm for central nervous system regeneration? Cell Mol Life Sci 2013; 70(20): 3871-82.
[http://dx.doi.org/10.1007/s00018-013-1290-8] [PMID: 23456256]
[28]
Mirotsou M, Jayawardena TM, Schmeckpeper J, Gnecchi M, Dzau VJ. Paracrine mechanisms of stem cell reparative and regenerative actions in the heart. J Mol Cell Cardiol 2011; 50(2): 280-9.
[http://dx.doi.org/10.1016/j.yjmcc.2010.08.005] [PMID: 20727900]
[29]
Cantaluppi V, Biancone L, Quercia A, Deregibus MC, Segoloni G, Camussi G. Rationale of mesenchymal stem cell therapy in kidney injury. Am J Kidney Dis 2013; 61(2): 300-9.
[http://dx.doi.org/10.1053/j.ajkd.2012.05.027] [PMID: 22938846]
[30]
Aghamohammadi D, Sharifi S, Shakouri SK, Eslampour Y, Dolatkhah N. Autologous conditioned serum (Orthokine) injection for treatment of classical trigeminal neuralgia: results of a single-center case series. J Med Case Reports 2022; 16(1): 183.
[http://dx.doi.org/10.1186/s13256-022-03393-9] [PMID: 35526052]
[31]
Alvarez-Camino JC, Vázquez-Delgado E, Gay-Escoda C. Use of autologous conditioned serum (Orthokine) for the treatment of the degenerative osteoarthritis of the temporomandibular joint. Review of the literature. Med Oral Patol Oral Cir Bucal 2013; 18(3): e433-8.
[http://dx.doi.org/10.4317/medoral.18373] [PMID: 23524415]
[32]
Godek P. Use of autologous serum in treatment of lumbar radiculopathy pain. Pilot Study. Ortop Traumatol Rehabil 2016; 18(1): 11-20.
[http://dx.doi.org/10.5604/15093492.1198829] [PMID: 27053305]
[33]
Becker C, Heidersdorf S, Drewlo S, de Rodriguez SZ, Krämer J, Willburger RE. Efficacy of epidural perineural injections with autologous conditioned serum for lumbar radicular compression: An investigator-initiated, prospective, double-blind, reference-controlled study. Spine 2007; 32(17): 1803-8.
[http://dx.doi.org/10.1097/BRS.0b013e3181076514] [PMID: 17762286]
[34]
Zhan J, Mann T, Joost S, Behrangi N, Frank M, Kipp M. The cuprizone model. Dos and Do Nots Cells 2020; 9(4): 843.
[http://dx.doi.org/10.3390/cells9040843] [PMID: 32244377]
[35]
Bénardais K, Kotsiari A, Škuljec J, et al. Cuprizone [bis(cyclohexylidenehydrazide)] is selectively toxic for mature oligodendrocytes. Neurotox Res 2013; 24(2): 244-50.
[http://dx.doi.org/10.1007/s12640-013-9380-9] [PMID: 23392957]
[36]
Brousse B, Magalon K, Durbec P, Cayre M. Region and dynamic specificities of adult neural stem cells and oligodendrocyte precursors in myelin regeneration in the mouse brain. Biol Open 2015; 4(8): 980-92.
[http://dx.doi.org/10.1242/bio.012773] [PMID: 26142314]
[37]
Shamsi F, Zeraatpisheh Z, Alipour H, Nazari A, Aligholi H. The effects of minocycline on proliferation, differentiation and migration of neural stem/progenitor cells. Int J Neurosci 2020; 130(6): 601-9.
[http://dx.doi.org/10.1080/00207454.2019.1699083] [PMID: 31801401]
[38]
Le Belle JE, Orozco NM, Paucar AA, et al. Proliferative neural stem cells have high endogenous ROS levels that regulate self-renewal and neurogenesis in a PI3K/Akt-dependant manner. Cell Stem Cell 2011; 8(1): 59-71.
[http://dx.doi.org/10.1016/j.stem.2010.11.028] [PMID: 21211782]
[39]
Vega-Riquer JM, Mendez-Victoriano G, Morales-Luckie RA, Gonzalez-Perez O. Five decades of cuprizone, an updated model to replicate demyelinating diseases. Curr Neuropharmacol 2019; 17(2): 129-41.
[http://dx.doi.org/10.2174/1570159X15666170717120343] [PMID: 28714395]
[40]
Romanko MJ, Rothstein RP, Levison SW. Neural stem cells in the subventricular zone are resilient to hypoxia/ischemia whereas progenitors are vulnerable. J Cereb Blood Flow Metab 2004; 24(7): 814-25.
[http://dx.doi.org/10.1097/01.WCB.0000123906.17746.00] [PMID: 15241190]
[41]
Prozorovski T, Schulze-Topphoff U, Glumm R, et al. Sirt1 contributes critically to the redox-dependent fate of neural progenitors. Nat Cell Biol 2008; 10(4): 385-94.
[http://dx.doi.org/10.1038/ncb1700] [PMID: 18344989]
[42]
Zhou D, Shao L, Spitz DR. Reactive oxygen species in normal and tumor stem cells. In: Advances in cancer research. Amsterdam: Elsevier 2014; pp. 1-67.
[43]
Nugud A, Sandeep D, El-Serafi AT. Two faces of the coin: Minireview for dissecting the role of reactive oxygen species in stem cell potency and lineage commitment. J Adv Res 2018; 14: 73-9.
[http://dx.doi.org/10.1016/j.jare.2018.05.012] [PMID: 30023134]
[44]
Tahmasebi F, Pasbakhsh P, Barati S, Madadi S, Kashani IR. The effect of microglial ablation and mesenchymal stem cell transplantation on a cuprizone‐induced demyelination model. J Cell Physiol 2021; 236(5): 3552-64.
[http://dx.doi.org/10.1002/jcp.30090] [PMID: 32996165]
[45]
Kipp M, Clarner T, Dang J, Copray S, Beyer C. The cuprizone animal model: New insights into an old story. Acta Neuropathol 2009; 118(6): 723-36.
[http://dx.doi.org/10.1007/s00401-009-0591-3] [PMID: 19763593]
[46]
Clarner T, Janssen K, Nellessen L, et al. CXCL10 triggers early microglial activation in the cuprizone model. J Immunol 2015; 194(7): 3400-13.
[http://dx.doi.org/10.4049/jimmunol.1401459] [PMID: 25725102]
[47]
Ahmed NEMB, Murakami M, Hirose Y, Nakashima M. Therapeutic potential of dental pulp stem cell secretome for alzheimer’s disease treatment: An in vitro study. Stem Cells Int 2016; 2016: 8102478.
[http://dx.doi.org/10.1155/2016/8102478] [PMID: 27403169]
[48]
Steelman AJ, Thompson JP, Li J. Demyelination and remyelination in anatomically distinct regions of the corpus callosum following cuprizone intoxication. Neurosci Res 2012; 72(1): 32-42.
[http://dx.doi.org/10.1016/j.neures.2011.10.002] [PMID: 22015947]
[49]
Wang J, Sun Y. Improving explicit term matching with implicit topic matching for short text conversation. Proc Assoc Inf Sci Technol 2019; 56(1): 286-95.
[http://dx.doi.org/10.1002/pra2.23]
[50]
Glenn JD, Smith MD, Kirby LA, Baxi EG, Whartenby KA. Disparate effects of mesenchymal stem cells in experimental autoimmune encephalomyelitis and cuprizone-induced demyelination. PLoS One 2015; 10(9): e0139008.
[http://dx.doi.org/10.1371/journal.pone.0139008] [PMID: 26407166]
[51]
Tanna T, Sachan V. Mesenchymal stem cells: potential in treatment of neurodegenerative diseases. Curr Stem Cell Res Ther 2014; 9(6): 513-21.
[http://dx.doi.org/10.2174/1574888X09666140923101110] [PMID: 25248677]
[52]
Bai L, Lennon DP, Eaton V, et al. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009; 57(11): 1192-203.
[http://dx.doi.org/10.1002/glia.20841] [PMID: 19191336]
[53]
Jaramillo-Merchán J, Jones J, Ivorra JL, et al. Mesenchymal stromal-cell transplants induce oligodendrocyte progenitor migration and remyelination in a chronic demyelination model. Cell Death Dis 2013; 4(8): e779.
[http://dx.doi.org/10.1038/cddis.2013.304] [PMID: 23990019]
[54]
Uccelli A, et al. Mesenchymal stem cells shape microglia effector functions through the release of CX-3CL1. Cell J (Yakhteh) 2013; 15 (Suppl. 1): 7-18.
[55]
Noh MY, Lim SM, Oh KW, et al. Mesenchymal stem cells modulate the functional properties of microglia via TGF-β secretion. Stem Cells Transl Med 2016; 5(11): 1538-49.
[http://dx.doi.org/10.5966/sctm.2015-0217] [PMID: 27400795]

Rights & Permissions Print Cite
© 2025 Bentham Science Publishers | Privacy Policy