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


Cite item

Full Text

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.

Conclusions: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.

About the authors

Omid Alavi

Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences

Email: info@benthamscience.net

Aliakbar Alizadeh

Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

Farzaneh Dehghani

Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences

Author for correspondence.
Email: info@benthamscience.net

Hamed Alipour

Department of Tissue Engineering, School of Advanced Medical Sciences and Technologies, Shiraz University of Medical Sciences

Email: info@benthamscience.net

Nader Tanideh

Stem Cells Technology Research Center, Shiraz University of Medical Sciences

Email: info@benthamscience.net

References

  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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 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. doi: 10.5966/sctm.2015-0217 PMID: 27400795

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2024 Bentham Science Publishers