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

Home/2022, Vol. 10, No. 1/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

Cell and Organ Transplantology. 2022; 10(1):in press.
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


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


1. Sulzev D, Surmeiter DJ. Neuronal vulnerability, pathogenests and Parkinson’s disease. Mov Disord. 2013. 28. P.715-724. doi: 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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:
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.
19. Prockop DJ, Phinney DG, Bunnel BA. Mesenchymal stem cells: method and protocols.-Totowa, NJ:Humana Press,2008.-192 p.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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
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.
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.
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.
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.
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.
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.
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.
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.
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):in press. doi:10.22494/cot.v10i1.134

Creative Commons License
Is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.