Wharton’s jelly mesenchymal stem cells attenuate global hypoxia-induced learning and memory impairment via preventing blood-brain barrier breakdown

Document Type : Original Article

Authors

1 Hubei Key Laboratory of Embryonic Stem Cell Research, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China

2 Department of Histology and Embryology, Faculty of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China

3 School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

4 Department of Anatomy, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran

5 Department of Neuroscience and Addiction Studies, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Tehran, Iran

Abstract

Objective(s): Intracerebroventricular (ICV) injections of mesenchymal stem cells (MSCs) may improve the function and structure of blood-brain barrier (BBB), possibly by preserving the BBB integrity. This study examined the impact of Wharton’s jelly (WJ)-MSCs on cognitive dysfunction and BBB disruption following a protracted hypoxic state.
Materials and Methods: Twenty-four male Wistar rats were randomly studied in four groups: Control (Co): Healthy animals, Sham (Sh): Rats were placed in the cage without hypoxia induction and with ICV injection of vehicle, Hypoxic (Hx)+vehicle: Hypoxic rats with ICV injection of vehicle (5 μl of PBS), and Hx+MSCs: Hypoxic rats with ICV injection of MSCs. Spatial learning and memory were evaluated one week after WJ-MSCs injection, and then animals were sacrificed for molecular research.
Results: Hypoxia increased latency and lowered the time and distance required reaching the target quarter, according to the findings. Furthermore, hypoxic rats had lower gene expression and protein levels of hippocampus vascular endothelial (VE)-cadherin, claudin 5, and tricellulin gene expression than Co and Sh animals (P<0.05). Finally, administering WJ-MSCs after long-term hypoxia effectively reversed the cognitive deficits and prevented the BBB breakdown via the upregulation of VE-cadherin, claudin 5, and tricellulin genes (P<0.05).
Conclusion: These findings suggest that prolonged hypoxia induces spatial learning and memory dysfunction and increases BBB disruption, the potential mechanism of which might be via reducing VE-cadherin, claudin 5, and tricellulin genes. Hence, appropriate treatment with WJ-MSCs could reverse ischemia adverse effects and protect the BBB integrity following prolonged hypoxia.

Keywords

Main Subjects

References

1. Wong AD, Ye M, Levy AF, Rothstein JD, Bergles DE, Searson PC. The blood-brain barrier: An engineering perspective. Front Neuroeng 2013;6:7.
2. Bernacki J, Dobrowolska A, Nierwińska K, Małecki A. Physiology and pharmacological role of the blood-brain barrier. Pharmacol Rep 2008;60:600-622.
3. Abbott NJ, Rönnbäck L, Hansson E. Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 2006;7:41-53.
4. Nadal A, Fuentes E, Pastor J, McNaughton PA. Plasma albumin is a potent trigger of calcium signals and DNA synthesis in astrocytes. Proc Natl Acad Sci USA 1995;92:1426-1430.
5. Gingrich MB, Junge CE, Lyuboslavsky P, Traynelis SF. Potentiation of NMDA receptor function by the serine protease thrombin. J Neurosci 2000;20:4582-4595.
6. Kadry H, Noorani B, Cucullo L. A blood-brain barrier overview on structure, function, impairment, and biomarkers of integrity. Fluids Barriers CNS. 2020;17:69-92.
7. Schulze C, Firth JAJJocs. Immunohistochemical localization of adherens junction components in blood-brain barrier microvessels of the rat. J Cell Sci 1993;104:773-782.
8. Naser AN, Lu Q, Chen Y-HJTB. Trans-compartmental regulation of tight junction barrier function. Tissue Barriers 2022;2133880:1-8.
9. Cording J, Berg J, Käding N, Bellmann C, Tscheik C, Westphal JK, et al. In tight junctions, claudins regulate the interactions between occludin, tricellulin and marvelD3, which, inversely, modulate claudin oligomerization. J Cell Sci 2013;126:554-64.
10. Mineta K, Yamamoto Y, Yamazaki Y, Tanaka H, Tada Y, Saito K, et al. Predicted expansion of the claudin multigene family. FEBS Lett 2011;585:606-612.
11. Higashi T, Miller AL. Tricellular junctions: How to build junctions at the TRICkiest points of epithelial cells. Mol Biol Cell 2017;28:2023-2034.
12. Abbott NJ, Patabendige AA, Dolman DE, Yusof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiol Dis 2010;37:13-25.
13. Yamamoto K, Ando JJAJoP-H, Physiology C. Vascular endothelial cell membranes differentiate between stretch and shear stress through transitions in their lipid phases. Am J Physiol Heart Circ Physiol 2015;309:H1178-H1185.
14. Pan R, Yu K, Weatherwax T, Zheng H, Liu W, Liu KJJSr. Blood occludin level as a potential biomarker for early blood brain barrier damage following ischemic stroke. Sci Rep 2017;7:40331-40339.
15. Jiao X, He P, Li Y, Fan Z, Si M, Xie Q, et al. The role of circulating tight junction proteins in evaluating blood brain barrier disruption following intracranial hemorrhage. Dis Markers  2015;2015:860120-860131.
16. Al Ahmad A, Gassmann M, Ogunshola OO. Involvement of oxidative stress in hypoxia-induced blood-brain barrier breakdown. Microvasc Res 2012;84:222-225.
17. Didari T, Hassani S, Baeeri M, Kazemi V, Abdollahi M, Mojtahedzadeh M. Evaluation the cardiopulmonary markers in cecal ligation and puncture-induced sepsis in Wistar rats. J Contemp Med Sci 2020;6:242-248.
18. Mahmood BR, Allwsh TAJJCMS, Vol. Assessment of the HER2, PDL1 and oxidative stress levels at the menopausal status of newly diagnosed breast cancer patients. J Contemp Med Sci 2022;8:352-356.
19. Engelhardt S, Al-Ahmad AJ, Gassmann M, Ogunshola OO. Hypoxia selectively disrupts brain microvascular endothelial tight junction complexes through a hypoxia-inducible factor-1 (HIF-1) dependent mechanism. J Cell Physiol 2014;229:1096-1105.
20. van der Flier M, Stockhammer G, Vonk GJ, Nikkels PG, van Diemen-Steenvoorde RA, van der Vlist GJ, et al. Vascular endothelial growth factor in bacterial meningitis: Detection in cerebrospinal fluid and localization in postmortem brain. J Infect Dis 2001;183:149-153.
21. Folco EJ, Sukhova GK, Quillard T, Libby PJCr. Moderate hypoxia potentiates interleukin-1β production in activated human macrophages. Circ Res 2014;115:875-883.
22. Rigor RR, Beard Jr RS, Litovka OP, Yuan SYJAJoP-CP. Interleukin-1β-induced barrier dysfunction is signaled through PKC-θ in human brain microvascular endothelium. Am J Physiol Cell Physiol 2012;302:C1513-C1522.
23. Bauer AT, Bürgers HF, Rabie T, Marti HH. Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J Cereb Blood Flow Metab 2010;30:837-848.
24. Sweeney MD, Sagare AP, Zlokovic BVJNRN. Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol 2018;14:133-150.
25. Mahakizadeh S, Mokhtari T, Navaee F, Poorhassan M, Tajik A, Hassanzadeh G. Effects of chronic hypoxia on the expression of seladin-1/Tuj1 and the number of dark neurons of hippocampus. J Chem Neuroanat 2020;104:101744.
26. Liu Y, Chen Q. Senescent mesenchymal stem cells: Disease mechanism and treatment strategy. Curr Mol Biol Rep 2020;6:173-182.
27. Kokai LE, Marra K, Rubin JPJTR. Adipose stem cells: Biology and clinical applications for tissue repair and regeneration. Transl Res 2014;163:399-408.
28. Xu C, Fu F, Li X, Zhang SJIjon. Mesenchymal stem cells maintain the microenvironment of central nervous system by regulating the polarization of macrophages/microglia after traumatic brain injury. Int J Neurosci 2017;127:1124-1135.
29. Noori L, Arabzadeh S, Mohamadi Y, Mojaverrostami S, Mokhtari T, Akbari M, et al. Intrathecal administration of the extracellular vesicles derived from human Wharton’s jelly stem cells inhibit inflammation and attenuate the activity of inflammasome complexes after spinal cord injury in rats. Neurosci Res 2021;170:87-98.
30. Hernández A, García E. Mesenchymal stem cell therapy for Alzheimer’s disease. Stem Cells Int 2021;2021:7834421-7834432.
31. Mendes Filho D, dC Ribeiro P, Oliveira LF, de Paula DR, Capuano V, de Assunção TS, et al. Therapy with mesenchymal stem cells in Parkinson disease: History and perspectives. Neurologist 2018;23:141-147.
32. Petrou P, Kassis I, Ginzberg A, Hallimi M, Karussis D. Effects of mesenchymal stem cell transplantation on cerebrospinal fluid biomarkers in progressive multiple sclerosis. Stem Cells Transl Med 2022;11:55-58.
33. Li Y, Huang J, Wang J, Xia S, Ran H, Gao L, et al. Human umbilical cord-derived mesenchymal stem cell transplantation supplemented with curcumin improves the outcomes of ischemic stroke via AKT/GSK-3β/β-TrCP/Nrf2 axis. J Neuroinflammation 2023;20:49-71.
34. Shetty P, Cooper K, Viswanathan C. Comparison of proliferative and multilineage differentiation potentials of cord matrix, cord blood, and bone marrow mesenchymal stem cells. Asian J Transfus Sci 2010;4:14-24.
35. Arutyunyan I, Elchaninov A, Makarov A, Fatkhudinov T. Umbilical cord as prospective source for mesenchymal stem cell-based therapy. Stem Cells Int 2016;2016:6901286-6901302.
36. Couvelaire A, Apoplexy U. Obstetric-gynecologic eponyms. blood 1957 ;9:741.
37. McElreavey KD, Irvine AI, Ennis KT, McLean WH. Isolation, culture and characterisation of fibroblast-like cells derived from the Wharton’s jelly portion of human umbilical cord. Biochem Soc Trans 1991;19:29S
38. Marino L, Castaldi MA, Rosamilio R, Ragni E, Vitolo R, Fulgione C, et al. Mesenchymal stem cells from the wharton’s jelly of the human umbilical cord: Biological properties and therapeutic potential. Int J Stem Cells 2019;12:218-226.
39. Atkinson AJ, Jr. Intracerebroventricular drug administration. Transl Clin Pharmacol 2017;25:117-124.
40. Kim HS, Lee NK, Yoo D, Lee J, Choi SJ, Oh W, et al. Lowering the concentration affects the migration and viability of intracerebroventricular-delivered human mesenchymal stem cells. Biochem Biophys Res Commun 2017;493:751-757.
41. Park SE, Lee NK, Na DL, Chang JW. Optimal mesenchymal stem cell delivery routes to enhance neurogenesis for the treatment of Alzheimer’s disease: Optimal MSCs delivery routes for the treatment of AD. Histol Histopathol 2018;33:533-541.
42. Kim HJ, Cho KR, Jang H, Lee NK, Jung YH, Kim JP, et al. Intracerebroventricular injection of human umbilical cord blood mesenchymal stem cells in patients with Alzheimer’s disease dementia: A phase I clinical trial. Alzheimers Res Ther 2021;13:154-164.
43. Arab L, Fanni A, Nemati S, Arefian E, Ai J, Mokhtari T, et al. Human embryonic derived neural progenitor cells improves neurological scores following brain ischemia/reperfusion: Modulation of blood and brain tissue microRNA-210. J Contemp Med Sci 2020;6:103-108.
44. Mokhtari T, Akbari M, Malek F, Kashani IR, Rastegar T, Noorbakhsh F, et al. Improvement of memory and learning by intracerebroventricular microinjection of T3 in rat model of ischemic brain stroke mediated by upregulation of BDNF and GDNF in CA1 hippocampal region. Daru 2017;25:4-14.
45. Aghaei I, Saeedi Saravi SS, Ghotbi Ravandi S, Nozari M, Roudbari A, Dalili A, et al. Evaluation of prepulse inhibition and memory impairments at early stage of cirrhosis may be considered as a diagnostic index for minimal hepatic encephalopathy. Physiol Behav 2017;173:87-94.
46. Mokhtari T, Yue L-P, Hu L. Exogenous melatonin alleviates neuropathic pain-induced affective disorders by suppressing NF-κB/ NLRP3 pathway and apoptosis. Scientific reports. Sci Rep 2023;13:2111-2125.
47. Kushwah N, Jain V, Kadam M, Kumar R, Dheer A, Prasad D, et al. Ginkgo biloba L. prevents hypobaric hypoxia–induced spatial memory deficit through small conductance calcium-activated potassium channel inhibition: The role of ERK/CaMKII/CREB signaling. Front Pharmacol 2021;12: 669701-669714.
48. Wang X, Cui L, Ji X. Cognitive impairment caused by hypoxia: from clinical evidences to molecular mechanisms. Metab Brain Dis 2021;37:1-16.
49. Ghotbeddin Z, Tabandeh MR, Pourmahdi Borujeni M, Fahimi Truski F, Zalaki Ghorbani Pour MR, Tabrizian LJB, et al. Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats. Brain Behav 2021;11:e02078-e2087.
50. Hashimoto Y, Campbell M. Tight junction modulation at the blood-brain barrier: Current and future perspectives. Biochim Biophys Acta Biomembr 2020;1862:183298183308.
51. Park J, Jung S, Kim S-M, Park Iy, Bui NA, Hwang G-S, et al. Repeated hypoxia exposure induces cognitive dysfunction, brain inflammation, and amyloidβ/p-Tau accumulation through reduced brain O-GlcNAcylation in zebrafish. J Cereb Blood Flow Metab 2021;41:3111-3126.
52. Kuhlmann CR, Tamaki R, Gamerdinger M, Lessmann V, Behl C, Kempski OS, et al. Inhibition of the myosin light chain kinase prevents hypoxia-induced blood-brain barrier disruption. J Neurochem 2007;102:501-507.
53. Sun X, Feinberg MW. NF-κB and hypoxia: A double-edged sword in atherosclerosis. Am J Pathol 2012;181:1513-1517.
54. Peng X, Li C, Yu W, Liu S, Cong Y, Fan G, et al. Propofol attenuates hypoxia-induced inflammation in BV2 microglia by inhibiting oxidative stress and NF-κB/Hif-1α signaling. BioMed Res Int 2020;2020: 8978704-8978714.
55. Mokhtari T, Yue L-P, Hu L. Exogenous melatonin alleviates neuropathic pain-induced affective disorders by suppressing NF-κB/NLRP3 pathway and apoptosis. Sci Rep 2023;13:2111-2125.
56. Koong AC, Chen EY, Giaccia A. Hypoxia causes the activation of nuclear factor κB through the phosphorylation of IκBα on tyrosine residues. Cancer Res 1994;54:1425-1430.
57. Schmedtje JF, Ji Y-S, Liu W-L, DuBois RN, Runge M. Hypoxia induces cyclooxygenase-2 via the NF-κB p65 transcription factor in human vascular endothelial cells. J Biol Chem 1997;272:601-608.
58. Cording J, Günther R, Vigolo E, Tscheik C, Winkler L, Schlattner I, et al. Redox regulation of cell contacts by tricellulin and occludin: redox-sensitive cysteine sites in tricellulin regulate both tri- and bicellular junctions in tissue barriers as shown in hypoxia and ischemia. Antioxid Redox Signal 2015;23:1035-1049.
59. Yang Z, Lin P, Chen B, Zhang X, Xiao W, Wu S, et al. Autophagy alleviates hypoxia-induced blood-brain barrier injury via regulation of CLDN5 (claudin 5). Autophagy 2021;17:3048-3067.
60. Ding DC, Chang YH, Shyu WC, Lin SZ. Human umbilical cord mesenchymal stem cells: A new era for stem cell therapy. Cell Transplant 2015;24:339-347.
61. de Castro LL, Lopes-Pacheco M, Weiss DJ, Cruz FF, Rocco P. Current understanding of the immunosuppressive properties of mesenchymal stromal cells. J Mol Med 2019;97:605-618.
62. Hsieh JY, Wang HW, Chang SJ, Liao KH, Lee IH, Lin WS, et al. Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PLoS One 2013;8:e72604-e72614.
63. Zhao Z, Wang Y, Peng J, Ren Z, Zhang L, Guo Q, et al. Improvement in nerve regeneration through a decellularized nerve graft by supplementation with bone marrow stromal cells in fibrin. Cell Transplant 2014;23:97-110.
64. Iyer SS, Rojas M. Anti-inflammatory effects of mesenchymal stem cells: Novel concept for future therapies. Expert Opin Biol Ther 2008;8:569-5981.
65. Li F, Zhang K, Liu H, Yang T, Xiao DJ, Wang YS. The neuroprotective effect of mesenchymal stem cells is mediated through inhibition of apoptosis in hypoxic ischemic injury. World J Pediatr 2020;16:193-200.
66. Cheng Z, Wang L, Qu M, Liang H, Li W, Li Y, et al. Mesenchymal stem cells attenuate blood-brain barrier leakage after cerebral ischemia in mice. J Neuroinflammation 2018;15:135-145.
67. Yang J, Ma K, Zhang C, Liu Y, Liang F, Hu W, et al. Burns impair blood-brain barrier and mesenchymal stem cells can reverse the process in mice. Front Immunol 2020;11:578879-578891.
68. Mehrannia K, Mokhtari T, Mogehi SMHN, Akbari M, Bazzaz JT, Mahakizeh S, et al. Intracerebroventricular injection of Wharton’s jelly mesenchymal stem cells attenuates brain damage in rat model of hypoxia: Optimization of vascular endothelial growth factor and downregulation of inflammatory factors. J Contemp Med Sci 2018;4:134-139.
69. Zhao Q, Gregory CA, Lee RH, Reger RL, Qin L, Hai B, et al. MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs. Proc Natl Acad Sci U S A 2015;112:530-535.
70. Pati S, Khakoo AY, Zhao J, Jimenez F, Gerber MH, Harting M, et al. Human mesenchymal stem cells inhibit vascular permeability by modulating vascular endothelial cadherin/β-catenin signaling. Stem Cells Dev 2011;20:89-101.
Iranian Journal of Basic Medical Sciences
Volume 26, Issue 9
September 2023
Pages 1053-1060

Files

Share

How to cite

Statistics