Influence of mesenchymal stromal cells of different origins on behavioural reactions of rats with cerebral ischemia-reperfusion

  • Received 01.03.2024

  • Revised 03.05.2024

  • Accepted 28.05.2024



  • 1,286 Views

  • Retrieved from Vol. 6, No. 2, 2024

  • Pages 16-24

A new direction in cell therapy for ischemic stroke has been the use of mesenchymal stromal cells, which have shown a positive impact on functional changes in the central nervous system due to their neuroprotective effects, reduction of ischemia-reperfusion-induced injury, inhibition of ischemia-reperfusion-induced apoptosis, and restoration of motor function. This study aimed to investigate the effect of mesenchymal stromal cells of different origins, their lysate, and citicoline on the functional state of the central nervous system in rats with experimental brain ischemia-reperfusion. The study considered the effect of mesenchymal stromal cells derived from human umbilical cord Wharton’s jelly, human and rat adipose tissue, rat embryonic fibroblasts, as well as mesenchymal stromal cell lysate and citicoline on the emotional and behavioural responses of sexually mature Wistar rats (3-4 months) weighing 160-190 g. The behavioural responses of rats were studied using the open field test on the 7th and 14th days of the experiment; the following behavioural acts were recorded: ambulation (locomotion), climbing, rearing, and grooming. The significance of differences was determined using the non-parametric Mann-Whitney U test. It was established that after ischemia-reperfusion, animals with control pathology showed a significant decrease in the duration of episodes of ambulation in peripheral and central squares, vertical locomotor activity, and exploratory activity compared to the sham-operated group. In rats that received citicoline and transplanted human umbilical cord Wharton’s jelly mesenchymal stromal cells, a significant increase in the duration of episodes of horizontal locomotor activity was observed compared to other types of stem cells and the control. Intravenous administration of rat embryonic fibroblasts increased the emotional activity of the experimental animals. The least impact on locomotor and adaptive exploratory activity in rats with ischemia-reperfusion was registered in groups of animals that received mesenchymal stromal cells from human and rat adipose tissue, as well as mesenchymal stromal cell lysate. The practical significance of the study lies in the search for the most effective class of stem cells with neuroprotective properties for the creation of an injectable drug for intravenous transplantation in the treatment of patients with acute ischemic stroke

stem cells; ischemia-reperfusion; adaptive behaviour; emotional activity; open field test

https://doi.org/10.61751/bmbr/2.2024.16

[1] Correction to: Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2020;141(2):e33.DOI: 10.1161/CIR.0000000000000746

[2] Correction to: Lancet Public Health 2022; 7:e74–85. Lancet Public Health. 2022;7(1):e14. DOI: 10.1016/S2468-2667(21)00281-4

[3] Zakrzewski W, Dobrzyński M, Szymonowicz M, Rybak Z. Stem cells: Past, present, and future. Stem Cell Res Ther. 2019;10(68). DOI: 10.1186/s13287-019-1165-5

[4] Zhang Y, Dong N, Hong H, Qi J, Zhang S, Wang J. Mesenchymal stem cells: Therapeutic mechanisms for stroke. Int J Mol Sci. 2022;23(5):2550. DOI: 10.3390/ijms23052550

[5] García-Bernal D, García-Arranz M, Yáñez RM, Hervás-Salcedo R, Cortés A, Fernández-García M, Hernando-Rodríguez M, et al. The current status of mesenchymal stromal cells: Controversies, unresolved issues and some promising solutions to improve their therapeutic efficacy. Front Cell Dev Biol. 2021;9:650664. DOI: 10.3389/fcell.2021.650664

[6] Pourmohammadi-Bejarpasi Z, Roushandeh AM, Saberi A, Rostami MK, Toosi SMR, Jahanian-Najafabadi A, et al. Mesenchymal stem cells-derived mitochondria transplantation mitigates I/R-induced injury, abolishes I/R-induced apoptosis, and restores motor function in acute ischemia stroke rat model. Brain Res Bull. 2020;165:70–80.DOI: 10.1016/j.brainresbull.2020.09.018

[7] Li J, Zhang Q, Wang W, Lin F, Wang S, Zhao J. Mesenchymal stem cell therapy for ischemic stroke: A look into treatment mechanism and therapeutic potential. J Neurol. 2021;268(11):4095–7. DOI: 10.1007/s00415-020-10138-5

[8] Chung JW, Chang WH, Bang OY, Moon GJ, Kim SJ, Kim SK, et al. Efficacy and safety of intravenous mesenchymal stem cells for ischemic stroke. Neurology. 2021;96(7), e1012–23. DOI: 10.1212/WNL.0000000000011440

[9] Cui LL, Golubczyk D, Tolppanen AM, Boltze J, Jolkkonen J. Cell therapy for ischemic stroke: Are differences in preclinical and clinical study design responsible for the translational loss of efficacy? Ann Neurol. 2019;86(1):5–16. DOI: 10.1002/ana.25493

[10] Hernando-Rodríguez M, Quintana-Bustamante Ó, Bueren JA, García-Olmo D, Moraleda JM, Segovia JC, Zapata AG. The current status of mesenchymal stromal cells: Controversies, unresolved issues and some promising solutions to improve their therapeutic efficacy. Front Cell Dev Biol. 2021;9:650664. DOI: 10.3389/fcell.2021.650664

[11] Derakhshankhah H, Sajadimajd S, Jafari S, Izadi Z, Sarvari S, Sharifi M, et al. Novel therapeutic strategies for Alzheimer's disease: Implications from cell-based therapy and nanotherapy. Nanomedicine (Lond). 2020;24:102149. DOI: 10.1016/j.nano.2020.102149

[12] Konovalov S, Moroz V, Konovalova N, Deryabina O, Shuvalova N, Toporova O, et al. The effect of mesenchymal stromal cells of various origins on mortality and neurologic deficit in acute ischemia-reperfusion in rats. Cell Organ Transplantol. 2021;9(2):104–8. DOI: 10.22494/cot.v9i2.132

[13] Konovalov S, Moroz V, Deryabina O, Shuvalova N, Tochylovsky A, Klymenko P, Kordium V. The effect of mesenchymal stromal cells of different origin on morphological parameters in the somatosensory cortex of rats with acute cerebral ischemia. Cell Organ Transplantol. 2023;11(1):46–52. DOI: 10.22494/cot.v11i1.149

[14] Chen Y, Peng D, Li J, Zhang L, Chen J, Wang L, Gao Y. A comparative study of different doses of bone marrow-derived mesenchymal stem cells improve post-stroke neurological outcomes via intravenous transplantation. Brain Res. 2023;1798:148161. DOI: 10.1016/j.brainres.2022.148161

[15] Bureš J, Burešová O, Huston JP. Techniques and basic experiments for the study of brain and behavior. Amsterdam: North Holland Biomedical Press; 2016. 290 p.

[16] Council of Europe. European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes [Internet]. 1986 [cited 2024 May 1]. ETS No. 123. 1986 Mar 18. Available from: https://rm.coe. int/168007a67b

[17] Law of Ukraine. On the Protection of Animals from Cruelty [Internet]. 2006 [cited 2024 May 1]. Order No. 3447-IV. 2006 Feb 21. Available from: https://zakon.rada.gov.ua/laws/show/3447-15#Text

[18] Koldunov V, Kozlova K, Klopotskyi H. Behavioral disorders in the open field test of female rats in the acute period of blast-induced traumatic brain injury. Prospects Innov Sci (Psychol, Pedag, Med). 2023;16(34):865–76. DOI: 10.52058/2786-4952-2023-16(34)-865-876

[19] Lei Q, Deng M, Liu J, He J, Lan Z, Hu Z, Xiao H. SRC3 promotes the protective effects of bone marrow mesenchymal stem cell transplantation on cerebral ischemia in a mouse model. ACS Chem Neurosci. 2022;13(1):112–19. DOI: 10.1021/acschemneuro.1c00599

[20] Tobin MK, Stephen TKL, Lopez KL, Pergande MR, Bartholomew AM, Cologna SM, Lazarov O. Activated mesenchymal stem cells induce recovery following stroke via regulation of inflammation and oligodendrogenesis. J Am Heart Assoc. 2020;9(7).e013583. DOI: 10.1161/JAHA.119.013583

[21] Guo Y, Peng Y, Zeng H, Chen G. Progress in mesenchymal stem cell therapy for ischemic stroke. Stem Cells Int. 2021;2021:9923566. DOI: 10.1155/2021/9923566

[22] Ntege EH, Sunami H, Shimizu Y. Advances in regenerative therapy: A review of the literature and future directions. Regen Ther. 2020;14:136–53. DOI: 10.1016/j.reth.2020.01.004

[23] He J, Liu J, Huang Y, Zhuo Y, Chen W, Duan D, et al. Olfactory mucosa mesenchymal stem cells alleviate cerebral ischemia/reperfusion injury via Golgi apparatus secretory pathway Ca2+ -ATPase isoform1. Front Cell Dev Biol. 2020;8:586541. DOI: 10.3389/fcell.2020.586541

[24] Zhou L, Zhu H, Bai X, Huang J, Chen Y, Wen J, et al. Potential mechanisms and therapeutic targets of mesenchymal stem cell transplantation for ischemic stroke. Stem Cell Res Ther. 2022;13(1):195. DOI: 10.1186/s13287-022-02876-2

[25] Brooks B, Ebedes D, Usmani A, Gonzales-Portillo JV, Gonzales-Portillo D, Borlongan CV. Mesenchymal stromal cells in ischemic brain injury. Cells. 2022;11(6):1013. DOI: 10.3390/cells11061013

[26] Nalamolu KR, Chelluboina B, Fornal CA, Challa SR, Pinson DM, Wang DZ, et al. Stem cell treatment improves post stroke neurological outcomes: A comparative study in male and female rats. Stroke Vasc Neurol. 2021;6(4):519–27. DOI: 10.1136/svn-2020-000834

[27] Nalamolu KR, Venkatesh I, Mohandass A, Klopfenstein JD, Pinson DM, Wang DZ, et al. Exosomes secreted by the cocultures of normal and oxygen-glucose-deprived stem cells improve post-stroke outcome. Neuromol Med. 2019;21(4):529–39. DOI: 10.1007/s12017-019-08540-y

[28] Ogawa Y, Okinaka Y, Takeuchi Y, Saino O, Kikuchi-Taura A, Taguchi A. Intravenous bone marrow mononuclear cells transplantation improves the effect of training in chronic stroke mice. Front Med. 2020;7:535902. DOI: 10.3389/fmed.2020.535902

[29] Ogawa Y, Saino O, Okinaka Y, Kikuchi-Taura A, Takeuchi Y, Taguchi A. Bone marrow mononuclear cells transplantation and training increased transplantation of energy source transporters in chronic stroke. J Stroke Cerebrovasc Dis. 2021;30(8):105932. DOI: 10.1016/j.jstrokecerebrovasdis.2021.105932

[30] de Celis-Ruiz E, Fuentes B, Alonso de Leciñana M, Gutiérrez-Fernández M, Borobia AM, Gutiérrez-Zúñiga R, et al. Final results of allogeneic adipose tissue-derived mesenchymal stem cells in acute ischemic stroke (AMASCIS): A phase II, randomized, double-blind, placebo-controlled, single-center, pilot clinical trial. Cell Transplant. 2022;31:9636897221083863. DOI: 10.1177/09636897221083863

[31] Zheng J, Mao X, Wang D, Xia S. Preconditioned MSCs alleviate cerebral ischemia-reperfusion injury in rats by improving neurological function and inhibiting apoptosis. Brain Sci. 2022;12(5):631. DOI: 10.3390/brainsci12050631

[32] Chen J-R, Cheng G-Y, Sheu C-C, Tseng G-F, Wang T-J, Huang Y-S. Transplanted bone marrow stromal cells migrate, differentiate and improve motor function in rats with experimentally induced cerebral stroke. J Anat. 2008 Sep;213(3):249–58. DOI: 10.1111/j.1469-7580.2008.00948.x

[33] Fu YS, Yeh CC, Chu PM, Chang WH, Lin MA, Lin YY. Xenograft of human umbilical mesenchymal stem cells promotes recovery from chronic ischemic stroke in rats. Int J Mol Sci. 2022;23(6):3149. DOI: 10.3390/ijms23063149