Cell and Organ Transplantology. 2022; 10(1):18-24.
DOI: 10.22494/cot.v10i1.134
The effects of transplanted adipose-derived multipotent mesenchymal stromal cells from mice of different age or from aging donors in combination with melatonin at experimental parkinsonism
Labunets I.1,2, Utko N.1,2, Panteleymonova T.1,2, Kyryk V.1,2, Kharkevych Yu.1,3, Rodnichenko A.1, Litoshenko Z.1,2, Butenko G.1,2
- 1State Institute of Genetic and Regenerative Medicine, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
- 2D. F. Chebotarev State Institute of Gerontology, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
- 3National University of Life and Environmental Sciences of Ukraine, Kyiv, Ukraine
Abstract
The transplantation of adipose-derived multipotent mesenchymal stromal cells (ADSCs) in Parkinson’s disease/parkinsonism is a promising area in their therapy. The effects of such cells may be influenced by the age of the donor and biologically active factors.
The purpose of the study is to compare the effect of transplanted ADSCs of donor mice of different age on the parameters of behaviour, oxidative stress and neuroinflammation in the brain of mice with an experimental model of parkinsonism; to evaluate changes in the effects of cells from older donors under the influence of exogenous hormone melatonin.
Materials and methods. The object of the study was adult (5-6 months) and aging (15-17 months) 129/Sv mice. Adult mice were injected once with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), and after 17 days – ADSCs of adult or aging donor mice at a dose of 700 thousand cells in the tail vein. Some mice received ADSCs of aging donors in combination with melatonin. Behavioural parameters were assessed in open-field, rigidity and rotarod tests; the relative content of macrophages was measured in the brain, malondialdehyde (MDA), the activity of antioxidant enzymes.
Results. Under the influence of MPTP, the number of squares, rearings, body length and length is significantly less than in the intact group, and muscle tone is higher; in the brain the content of MDA and macrophages increases and the activity of superoxide dismutase (SOD) decreases. After the transplantation of adult donor ADSCs, the parameters of body and step length increase significantly, but not to the level of intact mice; the activity of SOD, glutathione reductase (GR) and the proportion of macrophages increase in the brain. After the administration of ADSCs of aging donors, the values of behavioural parameters and the proportion of macrophages in the brain correspond to the control group (only MPTP), and the activity of SOD corresponds to intact animals. In mice treated with ADSCs of aging donors in combination with melatonin, the direction of changes in behavioural parameters, SOD and GR activity, macrophage percentage was similar to that observed after the administration of adult donor ADSCs.
Conclusions. The effects of ADSCs transplantation in mice with the MPTP model of parkinsonism depend on the age of the donor and are more pronounced in transplanted cells derived from adult mice. The effects of ADSCs from aging donors in combination with melatonin are consistent with those observed after administration of cells from adult donors.
Key words: adipose-derived multipotent mesenchymal stromal cells; MPTP; parkinsonism; melatonin; behavioral reactions; oxidative stress; macrophages
Full Text PDF1. Sulzev D, Surmeiter DJ. Neuronal vulnerability, pathogenests and Parkinson’s disease. Mov Disord. 2013. 28. P.715-724. doi: 10.1002/mds.25095. https://doi.org/10.1002/mds.25095 PMid:22791686 PMCid:PMC3578396 |
||||
2. Guo J-D, Zhao X, Li Y., Li G-R, Liu X-L. Damage to dopaminergic neurons by oxidative stress in Parkinson’s disease (Review). Int J Mol Med. 2018. 41.P.1817-1825. doi:10.3892/ijmm.2018.3406. https://doi.org/10.3892/ijmm.2018.3406 |
||||
3. Wang Q, Liu Y, Zhou J. Neuroinflammation in Parkinson’s disease and its potential as therapeutic target. Translat Neurodegenerat. 2015. 4:19. doi: 10.1186/s40035-015-0042-0. https://doi.org/10.1186/s40035-015-0042-0 PMid:26464797 PMCid:PMC4603346 |
||||
4. Li Zh, Cheung H-H. Stem cell-based therapies for Parkinson desease. Int J Mol Sci. 2020. 21, 8060. doi: 10.3390/ijms21218060. https://doi.org/10.3390/ijms21218060 PMid:33137927 PMCid:PMC7663462 |
||||
5. Konala V B, Mamidi M K, Bhonde R, Das A K, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome. Cytotherapy. 2016. 18. P. 13-24. DOI:10.1016/j.jcyt.2015.10.008. https://doi.org/10.1016/j.jcyt.2015.10.008 PMid:26631828 PMCid:PMC4924535 |
||||
6. Zachar L, Bacenlova D, Rosocher I. Activation, homing and role of the mesenchymal stem cells in the inflammatory environment. J Inflamm Res. 2016. 9. P. 231-240. DOI:10.2147/JIR.S121994. https://doi.org/10.2147/JIR.S121994 PMid:28008279 PMCid:PMC5170601 |
||||
7. Wojtas E, Zachwieja A, Zwyrzykowska A, Kupczynski R, Marycz K. The application of mesenchymal progenitor stem cells in the reduction of oxidative stress in animals. Turk J Biol. 2017. 41. P. 12-19. DOI:10.3906/biy-1603-13. https://doi.org/10.3906/biy-1603-13 |
||||
8. Laroni A, Kerlego de Rosbo N, Uccelli A. Mesenchymal stem cells for the treatment of neurological diseases: immunoregulation beyond neuroprotection. Immunology letter. 2015. 168. P. 183-190. http://dx.doi.org/10.1016/j.imlet.2015.08.007. https://doi.org/10.1016/j.imlet.2015.08.007 PMid:26296458 |
||||
9. Scruggs B A, Semon J A, Zhang X, Zhang Sh, Bowles A S, Pandey A C, et al. Age of the donor reduces the ability of human adipose derived stem cells to alleviate symptoms in the experimental autoimmune encephalomyelitis mouse model. Stem Cells Transl Med. 2013. 2. P. 797-807. http://dx.doi.org/10.5966/sctm.2013-0026 https://doi.org/10.5966/sctm.2013-0026 PMid:24018793 PMCid:PMC3785264 |
||||
10. Li Yi, Wu Q, Wang Y, Li Li, Bu H, Bao J. Senescence of mesenchymal stem cells (Review). Int J Mol Med. 2017. 39. P.775-782. Doi:10.3892/ijmm.2017.2012. https://doi.org/10.3892/ijmm.2017.2912 PMid:28290609 |
||||
11. Hu Ch, Li L. Melatonin plays critical role in mesenchymal stem cell-based regenerative medicine in vitro and in vivo. Stem Cell Res Ther. 2019. 10. Article number 13. DOI: 10.1186/s13287-018-1114-8. https://doi.org/10.1186/s13287-018-1114-8 PMid:30635065 PMCid:PMC6329089 |
||||
12. Zhang S, Chen S, Li Y, Liu Y. Melatonin as a promising agent of regulatory stem cell biology and its application in disease therapy. Pharmacol Res. 2017. 117. P.252-260. DOI: 10.1016/jphrs.2016.12.035. https://doi.org/10.1016/j.phrs.2016.12.035 PMid:28042087 |
||||
13. Labunets IF, Chaikovsky YuB, Savosko SI, Butenko GM, Sagach VF, Kop’yak BS. Effects of melatonin on the behavioral indices and structural characteristics of cerebral and spinal neurons of rats with experimental hemiparkinsonism. Neurophysiology. 2018. №1 (50). P.11-22. doi: 10.1007/s11062-018-9712-8. https://doi.org/10.1007/s11062-018-9712-8 |
||||
14. Labunets IF. Neuroprotective еffects of the pineal hormone melatonin in animals with experimental model of neurodegenerative pathology. Conceptual options for the development of medical science and education. Baltija Bublishing. 2020. P.355-370. doi: 10.30525/978-9934-588-44-01/18. https://doi.org/10.30525/978-9934-588-44-0/18 |
||||
15. Zeng XS, Geng WSh, Jia JJ. Neurotoxin-induced animal models of Parkinson disease: pathogenic mechanism and assessment. ASN Neuro. 2018. 10. P.1-15. doi:10.1177/175909/418777438. https://doi.org/10.1177/1759091418777438 PMid:29809058 PMCid:PMC5977437 |
||||
16. Meredith GE, Rademacher DJ. MPTP mouse models of Parkinson’s disease: an update. J Parkinsons Dis. 2011.1(1). P.19-33. doi:10.3233/JPD-2011-11023. https://doi.org/10.3233/JPD-2011-11023 PMid:23275799 PMCid:PMC3530193 |
||||
17. Labunets IF. Behavioral features in the mice of various strains and sex with model of parkinsonism. Fiziol Zh. 2020. 66(1). С.18-24. DOI: https://doi.org/10.15407/fz. https://doi.org/10.15407/fz |
||||
18. Labunets IF, Utko NA, Savosko SI, Panteleymonova TN, Butenko GM. Changes in nigral neuronal structure, indices of antioxidant protection of the brain and behavior in mice of different age with MPTP parkinsonism model. International neurological journal. 2020. №3 (16). P.7-15. doi: 10.22141/2224-0713.16.3.2020.203444. https://doi.org/10.22141/2224-0713.16.3.2020.203444 |
||||
19. Prockop DJ, Phinney DG, Bunnel BA. Mesenchymal stem cells: method and protocols.-Totowa, NJ:Humana Press,2008.-192 p. https://doi.org/10.1007/978-1-60327-169-1 |
||||
20. Родніченко АЄ. Деякі біологічні властивості мультипотентних мезенхімальних стромальних клітин кісткового мозку та жирової тканини мишей лінії FVB/N. Клітинна та органна трансплантологія. 2017. 5(2).С.188-193. Doi:10.22494/cot.v5i2.77. https://doi.org/10.22494/cot.v5i2.77 |
||||
21. Dominici M, LeBlanc K, Mueller I. Minimal criteria for defining multipotent mesenchymal stromal cells. The International society for cellular therapy position statement. Cytoterapy.2006. 8(4). P.315-317. Doi:10.1080/14653240600855905 https://doi.org/10.1080/14653240600855905 PMid:16923606 |
||||
22. Fernagut PO, Diguet E, Labattu B, Tison F. A simple method to measure stride length as an index of nigrostrial dysfunction in mice. J Neurosci Methods. 2002. 113(2). Р.123-130. DOI: 10.1016/s0165-0270(01)00485-x. https://doi.org/10.1016/S0165-0270(01)00485-X |
||||
23. Uchiyama M., Mihara M. Determination of malonaldehyde precursor in tissues by thiobarbituric acid test. Anal Biochem. 1978. 86(1). P. 271-278. DOI: 10.1016/0003-2697(78)90342-1. https://doi.org/10.1016/0003-2697(78)90342-1 |
||||
24. Rodriguez-Cruz A, Vesin D, Ramon-Luing L, Zuniga J, Quesniaux VFJ, Ryffel B. et al. CD3+ macrophages deliver proinflammatory cytokines by a CD3- and transmembrane TNF-dependent pathway and are increased at the BCG-infection site. Front Immunol. 2019. 10. Article 2550. doi:10.3389/fimmu.2019.02550. https://doi.org/10.3389/fimmu.2019.02550 PMid:31787969 PMCid:PMC6855269 |
||||
25. Li K, Li X, Shi G, Lei X, Huang Y, Bai L, Qin Ch. Effectiveness and mechanisms of adipose-derived stem cell therapy in animal models of Parkinson’s desease: a systematic review and meta-analysis. Translat Neurodegenerat. 2021.10:14. Doi.org/10.1186/s40035-021-00238-1. https://doi.org/10.1186/s40035-021-00238-1 PMid:33926570 PMCid:PMC8081767 |
||||
26. Park H, Chang KA. Therapeutic Potential of Repeated Intravenous Transplantation of Human Adipose-Derived Stem Cells in Subchronic MPTP- induced Parkinson’s Disease Mouse Model. Int J Mol Sci.2020. 21,8129. doi:10.3390/ijms21218129. https://doi.org/10.3390/ijms21218129 PMid:33143234 PMCid:PMC7663651 |
||||
27. Chi K,, Fu R-H, Huang Yu-Ch, Chen Sh-Y, Hsu Ch-J, Lin Sh-Z et al. Adipose-derived Stem Cells Stimulated with n-Butylidenephthalide Exhibit Therapeutic Effects in a Mouse Model of Parkinson’s Disease. Cell Transplantation. 2018. 27(3). P. 456-470. Doi:10.1177/0963689718757408. https://doi.org/10.1177/0963689718757408 PMid:29756519 PMCid:PMC6038049 |
||||
28. Angeloni C, Gatti M, Prata C, Hrelia S, Maraldi T. Role of mesenchymal stem cells in counteracting oxidative stress-related neurodegeneration. Int J Mol Sci. 2020. 21,3299. doi:10.3390/ijms21093299. https://doi.org/10.3390/ijms21093299 PMid:32392722 PMCid:PMC7246730 |
||||
29. Munoz MF, Arguelles S, Medina R, Cano M, Ayala A. Adipose-derived stem cells decreased nicroglia activation and protected dopaminergic loss in rat lipopolysacccharide model. J Cell Physiol. 2019. 234. P.13762-13772. Doi.org/10.1002/jcp.28055. https://doi.org/10.1002/jcp.28055 PMid:30637730 |
||||
30. Chierchia A, Chirico N, Boeri L, Raimondi I, Riva GA, Raimondi MT. et al. Secretome released from hydrogel-embedded adipose mesenchymal stem cells protects against the Parkinson’s disease related toxin 6-hydroxydopamine. Eur J Pharm Biopharm. 2017. 121.P.113-120. doi.org/10.1016/j.ejpb.2017.09.014. https://doi.org/10.1016/j.ejpb.2017.09.014 PMid:28965958 PMCid:PMC5656105 |
||||
31. Flaishon L., Hart G., Zelman E., Moussion Ch., Grabovsky V., Lapidot Tal G. et al. Anti-inflammatory effects of an inflammatory chemokine: CCL2 inhibits lymphocyte homing by modulation of CCL21-triggered integrin-mediated adhesions. Blood. 2008. 112(13).P.5016-5025. doi: 10.1182/blood-2007-12-129122. https://doi.org/10.1182/blood-2007-12-129122 PMid:18802011 |
||||
32. Praet J, Guglielmetti C., Berneman Z. Cellular and molecular neuropathology of the cuprizone mouse model: clinical relevance for multiple sclerosis. J Neubiorev. 2014. 47. P.485-505. Doi:10.1016/jneubiorev.2014.10.004 https://doi.org/10.1016/j.neubiorev.2014.10.004 PMid:25445182 |
||||
33. Zhang D, He Sh, Wang Q, Pu Sh, Zhou Z, Wu Q. Impact of aging on the characterization of brown and white adipose tissue-derived stem cells in mice. Cells tisuess organs.2020. Published online:June 11,2020. doi 10.1159/000507434. https://doi.org/10.1159/000507434 PMid:32526740 |
||||
34. Fatian-Labora JA, Morente-Lopez M, Arufe MC. Effect of aging on behaviour of mesenchymal stem cells. World J Stem cells.2019. 11(6). P.337-346. doi:10.4252/wjsc.v11.16.337. https://doi.org/10.4252/wjsc.v11.i6.337 PMid:31293716 PMCid:PMC6600848 |
||||
35. Labunets IF, Utko NA, Toporova OK. Effects of multipotent mesenchymal stromal cells of the human umbilical cord and their combination with melatonin in adult and aging mice with a toxic cuprizone model of demyelination. Adv Gerontol. 2021.11(2).P.173-180.doi:10.1134/S2079057021020077. https://doi.org/10.1134/S2079057021020077 |
||||
36. Yu X, Li Zh,Zheng H, Ho J, Chan M TV, Wu W K K. Protective roles of melatonin in central nervous system disease by regulation of neural stem cells. Cell prolif. 2017. 50(2):e12323. DOI: 10.1111/cpr.12323. https://doi.org/10.1111/cpr.12323 PMid:27943459 PMCid:PMC6529065 |
||||
37. Chen D, Zhang T, Lee TH. Cellular mechanisms of melatonin: insight from neurodegenerative diseases. Biomolecules. 2020. 10.1158. doi:10.3390/biom 10081158. https://doi.org/10.3390/biom10081158 PMid:32784556 PMCid:PMC7464852 |
||||
38. Heo JS, Pyo S, Lim JA-Y, Yoon DW, Kim BY, Kim J-H et al. Biological effects of melatonin on human adipose-derived mesenchymal stem cells. Int J Mol Med. 2019. 44. P.2234-2244. Doi:10.3892/ijmm.2019.4356. https://doi.org/10.3892/ijmm.2019.4356 PMCid:PMC6844604 |
||||
39. Luchetti F, Canonico B, Bartolini D, Arcangeletti M, Ciffolilli S, Murdolo G. et al. Melatonin regulates mesenchymal stem cell differentiation: a review. J Pineal Res. 2014. 56. P. 382-397. DOI:10.1111/jpi.12133. https://doi.org/10.1111/jpi.12133 PMid:24650016 |
||||
40. Tan ShS, Han X, Sivakumaran P, Lim ShY, Morrison WA.Melatonin protects human adipose-derived stem cells from oxidative stress and cell death. APS.2016. 43 (3). P.237-241. Doi.org/10.5999/aps.2016.43.3.237. https://doi.org/10.5999/aps.2016.43.3.237 PMid:27218020 PMCid:PMC4876151 |
||||
Labunets I, Utko N, Panteleymonova T, Kyryk V, Kharkevych Yu, Rodnichenko A, Litoshenko Z, Butenko G. Effects of transplanted adipose-derived multipotent mesenchymal stromal cells from mice of different age or from aging donors in combination with melatonin at experimental parkinsonism. Cell Organ Transpl. 2022; 10(1):18-24. Available from: https://doi.org/10.22494/cot.v10i1.134
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