Cell and Organ Transplantology. 2023; 11(1):46-52.
DOI: 10.22494/cot.v11i1.149
The effect of mesenchymal stromal cells of different origin on morphological parameters in the somatosensory cortex of rats with acute cerebral ischemia
Konovalov S.1
, Moroz V.1
, Deryabina O.2
, Shuvalova N.2
, Tochylovsky A.3, Klymenko P.2,4
, Kordium V.2,5![]()
- 1National Pirogov Memorial Medical University, Vinnytsya, Ukraine
- 2Institute of Genetic and Regenerative Medicine, M. D. Strazhesko National Scientific Center of Cardiology, Clinical and Regenerative Medicine, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine Kyiv, Ukraine
- 3BioTexCom LLC, Kyiv, Ukraine
- 4D. F. Chebotarev State Institute of Gerontology, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
- 5Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine
Abstract
Ischemic stroke is the second leading cause of death and the leading cause of disability worldwide. So far, promising experimental data have been obtained regarding the elimination of neurological dysfunction and the reduction of the area of ischemic damage when using mesenchymal stromal cells (MSCs).
Purpose: to characterize the effects of MSCs of different origin, lysate of human Wharton’s jelly-derived MSCs and citicoline on the dynamics of destructive changes in the somatosensory cortex of rats with acute cerebrovascular accident according to light microscopy and micromorphometry data.
Materials and methods. An experiment was performed using 4-month-old male Wistar rats weighing 160-190 g, which were subjected to transient bilateral 20-minute ischemia-reperfusion (IR) of the internal carotid arteries. After modeling the pathology, the animals were injected into the femoral vein with obtained from human umbilical cord Wharton’s jelly-derived MSCs, human and rat adipose tissue-derived MSCs at a dose of 106 cells/animal. Other groups of experimental animals were intravenously injected with fetal rat fibroblasts at a dose of 106 cells/animal in 0.2 mL of saline and lysate of human umbilical cord Wharton’s jelly-derived MSCs at a dose of 0.2 mL/animal. Control animals were injected IV with 0.2 ml of physiological solution. The last group of rats received a single dose of the reference drug citicoline at a dose of 250 mg/kg. The morphometric studies were conducted on the 7th and 14th day. In the somatosensory cortex, the total number of neuron nuclei per 1 mm2 was counted, and the ratio of the number of intact neuron nuclei and nuclei with pathological changes (karyorrhexis and karyopyknosis) was also determined.
Results. The transplantation of stem cells, lysate of human umbilical cord Wharton’s jelly-derived MSCs, or citicoline contributed to an increase in the number of neurons with nuclei in the somatosensory cortex, as well as an increase in the number of nuclei that did not undergo pathological changes. The transplantation of human umbilical cord Wharton’s jelly-derived MSCs had the most positive effect. The number of neuron nuclei in 1 mm2 that did not undergo pathological changes in the somatosensory cortex in this group of animals approached the number of nuclei in the group of pseudo-operated animals, while the number of nuclei that did not undergo pathological changes significantly exceeded the number of nuclei with signs of destruction.
Conclusion: A significant increase in the number of neurons without signs of pathological changes was observed in all experimental groups of rats during the modeling of ischemic brain injury after the injection of various types of studied mesenchymal stromal cells, lysate or citicoline. The most positive result in the somatosensory cortex was achieved after the transplantation of human umbilical cord Wharton’s jelly-derived MSCs.
Key words: somatosensory cortex; ischemic stroke; mesenchymal stromal cells; cell transplantation
Full Text PDF| 1. Katan M, Luft A. Global Burden of Stroke. Semin Neurol. 2018 Apr;38(2):208-211. doi: 10.1055/s-0038-1649503. Epub 2018 May 23. PMID: 29791947. https://doi.org/10.1055/s-0038-1649503 PMid:29791947 |
||||
| 2. Wafa HA, Wolfe CDA, Emmett E, Roth GA, Johnson CO, Wang Y. Burden of Stroke in Europe: Thirty-Year Projections of Incidence, Prevalence, Deaths, and Disability-Adjusted Life Years. Stroke. 2020 Aug;51(8):2418-2427. doi: 10.1161/STROKEAHA.120.029606. Epub 2020 Jul 10. PMID: 32646325; PMCID: PMC7382540. https://doi.org/10.1161/STROKEAHA.120.029606 PMid:32646325 PMCid:PMC7382540 |
||||
| 3. Virani SS, Alonso A, Aparicio HJ, Benjamin EJ, Bittencourt MS, Callaway CW, et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2021 Update: A Report From the American Heart Association. Circulation. 2021 Feb 23;143(8):e254-e743. doi: 10.1161/CIR.0000000000000950. Epub 2021 Jan 27. PMID: 33501848. https://doi.org/10.1161/CIR.0000000000000950 PMid:33501848 |
||||
| 4. https://phc.org.ua/news/29-zhovtnya-vsesvitniy-den-borotbi-z-insultom, центр громадського здоров’я. | ||||
| 5. Fricker, M.; Tolkovsky, A.M.; Borutaite, V.; Coleman, M.; Brown, G.C. Neuronal cell death. Physiol. Rev. 2018, 98, 813-880. https://doi.org/10.1152/physrev.00011.2017 https://doi.org/10.1152/physrev.00011.2017 PMid:29488822 PMCid:PMC5966715 |
||||
| 6. Anamaria Jurcau, Ioana Adriana Ardelean. Molecular pathophysiological mechanisms of ischemia/reperfusion injuries after recanalization therapy for acute ischemic stroke. J. Integr. Neurosci. 2021, 20(3), 727-744. https://doi.org/10.31083/j.jin2003078 https://doi.org/10.31083/j.jin2003078 PMid:34645107 |
||||
| 7. Liaw N, Liebeskind D. Emerging therapies in acute ischemic stroke. F1000Res. 2020 Jun 5;9:F1000 Faculty Rev-546. doi: 10.12688/f1000research.21100.1. PMID: 32551094; PMCID: PMC7276937. https://doi.org/10.12688/f1000research.21100.1 PMid:32551094 PMCid:PMC7276937 |
||||
| 8. Nam HS, Kwon I, Lee BH, Kim H, Kim J, An S, Lee OH, Lee PH, Kim HO, Namgoong H, Kim YD, Heo JH. Effects of Mesenchymal Stem Cell Treatment on the Expression of Matrix Metalloproteinases and Angiogenesis during Ischemic Stroke Recovery. PLoS One. 2015 Dec 4;10(12):e0144218. doi: 10.1371/journal.pone.0144218. Erratum in: PLoS One. 2016;11(1):e0146628. PMID: 26637168; PMCID: PMC4670145. https://doi.org/10.1371/journal.pone.0144218 PMid:26637168 PMCid:PMC4670145 |
||||
| 9. He B, Yao Q, Liang Z, Lin J, Xie Y, Li S, Wu G, Yang Z, Xu P. The Dose of Intravenously Transplanted Bone Marrow Stromal Cells Determines the Therapeutic Effect on Vascular Remodeling in a Rat Model of Ischemic Stroke. Cell Transplant. 2016 Dec 13;25(12):2173-2185. doi: 10.3727/096368916X692627. Epub 2016 Aug 1. PMID: 27480476. https://doi.org/10.3727/096368916X692627 PMid:27480476 |
||||
| 10. 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 Jan 1;1798:148161. doi: 10.1016/j.brainres.2022.148161. Epub 2022 Nov 12. PMID: 36379315. https://doi.org/10.1016/j.brainres.2022.148161 PMid:36379315 |
||||
| 11. Kawabori M, Kuroda S, Ito M, Shichinohe H, Houkin K, Kuge Y, Tamaki N. Timing and cell dose determine therapeutic effects of bone marrow stromal cell transplantation in rat model of cerebral infarct. Neuropathology. 2013 Apr;33(2):140-8. doi: 10.1111/j.1440-1789.2012.01335.x. Epub 2012 Jun 21. PMID: 22725254. https://doi.org/10.1111/j.1440-1789.2012.01335.x PMid:22725254 |
||||
| 12. Konovalov S, Moroz V, Deryabina O, Klymenko P, Tochylovsky A, Kordium V. The effect of mesenchymal stromal cells of various origins on morphology of hippocampal CA1 area of rats with acute cerebral ischemia. Cell Organ Transpl. 2022; 10(2):98-106. https://doi.org/10.22494/cot.v10i2.144 |
||||
| 13. Ходаковский АА. Особенности формирования постреперфузионного повреждения нейронов – характеристика модели «ишемия-реперфузия». Новые направления и перспективы развития современной церебропротекторной терапии ишемического инсульта /А.А. Ходаковский, Л.И. Маринич, О.В. Багаури //Врач-аспирант. 2013; 3 (58): 69-76 | ||||
| 14. Secades JJ. Citicoline: pharmacological and clinical review, 2016 update. Rev Neurol. 2016; 63(03): 1-73. PMID: 28417449. | ||||
| 15. Diederich K., Frauenknecht K., Minnerup J., et al. Citicoline enhances neuroregenerative processes after experimental stroke in rats [published correction appears in Stroke. 2012; 43(7): 1931-1940. DOI:10.1161/STROKEAHA.112.654806 https://doi.org/10.1161/STROKEAHA.112.654806 PMid:22581817 |
||||
| 16. Bustamante, A., Giralt, D., Garcia-Bonilla, L. et al. Citicoline in pre-clinical animal models of stroke: a meta-analysis shows the optimal neuroprotective profile and the missing steps for jumping into a stroke clinical trial. Journal of neurochemistry. 2012; 123(2): 217-225. https://doi.org/10.1111/j.1471-4159.2012.07891.x https://doi.org/10.1111/j.1471-4159.2012.07891.x PMid:22845688 |
||||
| 17. Mehta, A., Mahale, R., Buddaraju, K. et al. Efficacy of Neuroprotective Drugs in Acute Ischemic Stroke: Is It Helpful?. Journal of neurosciences in rural practice. 2019; 10(4): 576-581. https://doi.org/10.1055/s-0039-170079 https://doi.org/10.1055/s-0039-1700790 PMid:31831974 PMCid:PMC6906097 |
||||
| 18. Lee MC., Jin CY., Kim HS. et al. Stem cell dynamics in an experimental model of stroke. Chonnam medical journal. 2011; 47(2): 90-98. DOI.org/10.4068/cmj.2011.47.2.90 https://doi.org/10.4068/cmj.2011.47.2.90 PMid:22111067 PMCid:PMC3214868 |
||||
| 19. Педаченко Е., Мороз В., Яцык В., Маляр Ю., Любич Л. и Егорова Д. (2020). Использование аутологичных клеток для восстановления функциональных дефектов у больных с ишемическим нарушением мозгового кровообращения. Украинская интервенционная нейрорадиология и хирургия , 33 (3), 83-93. https://doi.org/10.26683/2304-9359-2020-3(33)-83-93 https://doi.org/10.26683/2304-9359-2020-3(33)-83-93 |
||||
| 20. Toyoshima, A., Yasuhara, T., Kameda, M., Morimoto, J., Takeuchi, H., Wang, F., Intra-arterial transplantation of allogeneic mesenchymal stem cells mounts neuroprotective effects in a transient ischemic stroke model in rats: analyses of therapeutic time window and its mechanisms. PLoS One 10:e0127302. doi: 10.1371/journal.pone.0127302 https://doi.org/10.1371/journal.pone.0127302 PMid:26075717 PMCid:PMC4468176 |
||||
| 21. 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 Mar 15;23(6):3149. doi: 10.3390/ijms23063149. PMID: 35328574; PMCID: PMC8953545. https://doi.org/10.3390/ijms23063149 PMid:35328574 PMCid:PMC8953545 |
||||
| 22. Marei HE, Hasan A, Rizzi R, Althani A, Afifi N, Cenciarelli C, Caceci T, Shuaib A. Potential of Stem Cell-Based Therapy for Ischemic Stroke. Front Neurol. 2018 Feb 6;9:34. doi: 10.3389/fneur.2018.00034. PMID: 29467713; PMCID: PMC5808289. https://doi.org/10.3389/fneur.2018.00034 PMid:29467713 PMCid:PMC5808289 |
||||
| 23. Arroyo A, Díez-Tejedor E, Gutiérrez-Fernández M; RESSTORE consortium. Intravenous delivery of adipose tissue-derived mesenchymal stem cells improves brain repair in hyperglycemic stroke rats. Stem Cell Res Ther. 2019 Jul 17;10(1):212. doi: 10.1186/s13287-019-1322-x. PMID: 31315686; PMCID: PMC6637493. https://doi.org/10.1186/s13287-019-1322-x PMid:31315686 PMCid:PMC6637493 |
||||
| 24. Asgari Taei A, Nasoohi S, Hassanzadeh G, Kadivar M, Dargahi L, Farahmandfar M. Enhancement of angiogenesis and neurogenesis by intracerebroventricular injection of secretome from human embryonic stem cell-derived mesenchymal stem cells in ischemic stroke model. Biomed Pharmacother. 2021 Aug;140:111709. doi: 10.1016/j.biopha.2021.111709. Epub 2021 May 18. PMID: 34020250. https://doi.org/10.1016/j.biopha.2021.111709 PMid:34020250 |
||||
| 25. Seo HG, Yi Y, Oh BM, Paik NJ. Neuroprotective effect of secreted factors from human adipose stem cells in a rat stroke model. Neurol Res. 2017 Dec;39(12):1114-1124. doi: 10.1080/01616412.2017.1379293. Epub 2017 Sep 26. PMID: 28948857. https://doi.org/10.1080/01616412.2017.1379293 PMid:28948857 |
||||
| 26. Hsieh JY, Wang HW, Chang SJ, Liao KH, Lee IH, Lin WS, Wu CH, Lin WY, Cheng SM. Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One. 2013 Aug 22;8(8):e72604. doi: 10.1371/journal.pone.0072604. PMID: 23991127; PMCID: PMC3749979. https://doi.org/10.1371/journal.pone.0072604 PMid:23991127 PMCid:PMC3749979 |
||||
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 Transpl. 2023; 11(1):46-52. Available from: https://doi.org/10.22494/cot.v11i1.149

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

