Cell and Organ Transplantology. 2021; 9(2):104-108.
The effect of mesenchymal stromal cells of various origins on mortality and neurologic deficit in acute cerebral ischemia-reperfusion in rats
- 1National Pirogov Memorial Medical University, Vinnytsya, Ukraine
- 2State Institute of Genetic and Regenerative Medicine, National Academy of Medical Sciences of Ukraine, Kyiv, Ukraine
- 3Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Kyiv, Ukraine
- 4BioTexCom LLC, Kyiv, Ukraine
Stroke is a global epidemic issue and the second leading cause of death in the world and in Ukraine. According to official statistics, every year 100-110 thousand Ukrainians suffer acute cerebrovascular disorders. One third of such patients are of working age, up to 50 % will have a disability, and only one in ten will fully return to full life. So far, promising experimental data on the treatment of neurological dysfunction using mesenchymal stromal cells (MSCs) have been obtained.
The aim of study is to compare the effect of MSCs of different origins on mortality and neurologic deficit in rats with acute cerebral ischemia-reperfusion injury (CIRI).
Materials and methods. Acute cerebral ischemia-reperfusion was modeled by transient bilateral 20-minute occlusion of internal carotid arteries was modeled in male Wistar rats aged 4 months and animals were injected intravenously with 1·106 MSCs derived from human umbilical cord Wharton’s-jelly (hWJ-MSC), human and rat adipose tissue. Other groups of experimental animals were injected intravenously with rat fetal fibroblasts and cell lysate from hWJ-MSC. The last group of rats received Citicoline at a dose of 250 mg/kg as a reference drug. Control animals were injected intravenously with normal saline. The cerebroprotective effect of therapy was assessed by mortality and neurologic deficit in rats on the McGraw’s stroke index score.
Results. After 12 hours of observation in the crucial period in the development of experimental acute cerebrovascular disorders with the administration of hWJ-MSC, mortality was only 10 % against 45 % of animals in the control group. The use of rat fetal fibroblasts reduced the mortality of animals compare to the control group by an average of 25 %. CIRI in rats caused severe neurologic deficits: paralysis, paresis, ptosis, circling behavior. On the 7th day of observation in the control group of animals, the mean score on the McGrow’s stroke index indicated severe neurological disorders. On the 14th day of observation in this group of animals there was no complete recovery of lost central nervous system functions. Compared with the control group of animals, all the treatment agents for acute CIRI (MSCs of various origins, MSC’s lysate and Citicoline) contributed to a significant regression of neurologic deficit.
Conclusions. Thus, transplantation of human Wharton’s jelly-derived MSCs and rat fetal fibroblasts reduced mortality and alleviated neurological symptoms in rats with experimental ischemic stroke. hWJ-MSC, rat fetal fibroblasts, and rat adipose-derived MSCs reduced the incidence of neurological disorders better than Citicoline, which was accompanied by a regression of neurologic deficit dynamics on the 14th day of follow-up. The ability of stem cells of different origins to reduce neurologic deficit indicates the feasibility of their use in experimental acute cerebral ischemia.
Key words: ischemic stroke; cerebral ischemia-reperfusion injury, mesenchymal stromal cells; mortality; neurologic deficitFull Text PDF
|1. Available from: https://www.world-stroke.org/world-stroke-day-campaign/why-stroke-matters/learn-about-stroke|
|2. Available from: https://phc.org.ua/news/29-zhovtnya-vsesvitniy-den-borotbi-z-insultom, центр громадського здоров’я|
|3. Available from: https://www.kmu.gov.ua/news/stacionarne-likuvannya-gostrogo-mozkovogo-insultu-shcho-zminitsya-u-programi-medichnih-garantij-2021|
|4. Albers GW, Marks MP, Kemp S, et al. Thrombectomy for stroke at 6 to 16 hours with selection by perfusion imaging. N Engl J Med. 2018; 378:708-718. DOI: 10.1056/NEJMoa1713973
|5. Nogueira RG, Jadhav AP, Haussen DC, et al. Thrombectomy 6 to 24 hours after stroke with a mismatch between deficit and infarct. N Engl J Med. 2018; 378:11-21. DOI: 10.1056/NEJMoa1706442
|6. Cheng T, Yang B, Li D, et al. Wharton’s Jelly transplantation improves neurologic function in a rat model of traumatic brain injury. Cell Mol Neurobiol. 2015; 35:641-9.
|7. Donders R, Bogie JFJ, Ravanidis S, et al. Human Wharton’s Jelly-derived stem cells display a distinct immunomodulatory and proregenerative transcriptional signature compared to bone marrow-derived stem cells. Stem Cells Dev 2018; 27:65-84.
|8. He JQ, Sussman ES, Steinberg GK. Revisiting Stem Cell-Based Clinical Trials for Ischemic Stroke. Front Aging Neurosci. 2020; 12:575990. DOI: 10.3389/fnagi.2020.575990
|9. Wu KJ, Yu SJ, Chiang CW, et al. Neuroprotective action of human wharton’s jelly-derived mesenchymal stromal cell transplants in a rodent model of stroke. Cell Transplant. 2018; 27:1603-1612.
|10. Aggarwal S, Pittenger MF. Human mesenchymal stem cells modulate allogeneic immune cell responses. Blood. 2005; 105(4):1815-1822. DOI:10.1182/blood-2004-04-1559
|11. Tondreau T, Meuleman N, Delforge A, et al. Mesenchymal stem cells derived from CD133-positive cells in mobilized peripheral blood and cord blood: proliferation, Oct4 expression, and plasticity. Stem Cells. 2005; 23(8):1105-12. DOI: 10.1634/stemcells.2004-0330
|12. Zhang L, Wang LM, Chen WW, et al. Neural differentiation of human Wharton’s jelly-derived mesenchymal stem cells improves the recovery of neurological function after transplantation in ischemic stroke rats. Neural Regen Res. 2017; 12:1103-1110.
|13. Khodakovskij AA, Marinich LI, Bagauri OV. Features of the formation of post-reperfusion damage to neurons – a characteristic of the “ischemia-reperfusion” model. New directions and prospects for the development of modern cerebroprotective therapy for ischemic stroke. Doctor-graduate student. 2013; 3(58):69-76. [In Russian]|
|14. Tsymbaliuk VI, Deryabina OG, Shuvalova NS, Maslova OO, Pokholenko IaO, Toporova OK, et al. Phenotypical changes and proliferative potential of mesenchymal stem cells from humans Wharton’s jelly in the cultivation conditions. Ukr Neurosurg J. 2015; 2:17-24.
|15. Estes BT, Diekman BO, Gimble JM, Guilak F. Isolation of adipose derived stem cells and their induction to a chondrogenic phenotype. Nat Protoc. 2010; 5(7):1294-1311. DOI:10.1038/nprot.2010.81
|16. Kurzyk A, Dębski T, Święszkowski W, Pojda Z. Comparison of adipose stem cells sources from various locations of rat body for their application for seeding on polymer scaffolds. J Biomater Sci Polym Ed. 2019; 30(5):376-397. Available from: https://doi.org/10.1080/09205063.2019.1570433
|17. Weber SC, Gratop A, Akanbi S, Rheinlaender C, Sallmon H, Barikbin B, et al. Isolation and culture of fibroblasts, vascular smooth muscle, and endothelial cells from the fetal rat ductus arteriosus. Pediatr Res. 2011; 70(3):236-41. DOI: 10.1203/PDR.0b013e318225f748
|18. Diederich K, Frauenknecht K, Minnerup J, et al. Citicoline enhances neuroregenerative processes after experimental stroke in rats [published correction appears in Stroke. 2012; 43(11):e169]. Stroke. 2012; 43(7):1931-1940. DOI:10.1161/STROKEAHA.112.654806
|19. 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. J Neurochem. 2012; 123(2):217-225.
|20. 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.
|21. McGraw CP, Pashayan AG, Wendel OT. Cerebral infarction in the Mongolian gerbil exacerbated by phenoxybenzamine treatment. Stroke. 1976; 7(5):485-488.
|22. Lee MC, Jin CY, Kim HS, et al. Stem cell dynamics in an experimental model of stroke. Chonnam Med J. 2011; 47(2):90-98. DOI.org/10.4068/cmj.2011.47.2.90
|23. Ding DC, Shyu WC, Chiang MF, et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis. 2007; 27:339-53.
|24. Wu CJ, Wang ZY, Yang YX, Luan Z. Long-term effect of oligodendrocyte precursor cell transplantation on a rat model of white matter injury in the preterm infant. Zhongguo Dang Dai Er Ke Za Zhi. 2017; 19(9):1003-1007.
|25. 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. 2015; 10:e0127302. DOI: 10.1371/journal.pone.0127302
|26. Moisan A, Favre I, Rome C, De Fraipont F, Grillon E, Coquery N. Intravenous injection of clinical grade human MSCs after experimental stroke: functional benefit and microvascular effect. Cell Transplant. 2016; 25:2157-2171. DOI: 10.3727/096368916X691132
|27. Hu Y, Chen W, Wu L, Jiang L, Qin H, Tang N. Hypoxic preconditioning improves the survival and neural effects of transplanted mesenchymal stem cells via CXCL12/CXCR4 signalling in a rat model of cerebral infarction. Cell Biochem. Funct. 2019; 37:504-515. DOI: 10.1002/cbf.3423
|28. Son JW, Park J, Kim YE, Ha J, Park DW, Chang MS. Glia-like cells from late-passage human MSCs protect against ischemic stroke through IGFBP-4. Mol Neurobiol. 2019; 56:7617-7630. DOI: 10.1007/s12035-019-1629-8
Konovalov S, Moroz V, Konovalova N, Deryabina O, Shuvalova N, Toporova O, Tochylovsky A, Kordium V. The effect of mesenchymal stromal cells of various origins on mortality and neurologic deficit in acute cerebral ischemia-reperfusion in rats. Cell Organ Transpl. 2021; 9(2):104-108. doi:10.22494/cot.v9i2.132