Iranian Journal of Medical Sciences

Document Type : Original Article(s)

Authors

1 Doctoral Program Biomedical Science, Faculty of Medicine, Andalas University, Padang, Indonesia

2 Department of Medical Laboratory Technology, STIKES Syedza Saintika, Indonesia

3 Department of Anatomy, Faculty of Medicine, Andalas University, Padang, Indonesia

4 Department of Biochemistry, Faculty of Medicine, Andalas University, Padang, Indonesia

5 Clinical Pathology, Faculty of Medicine, Andalas University, Padang, Indonesia

10.30476/ijms.2023.98912.3104

Abstract

Background: Alzheimer’s disease (AD) is a neurodegenerative condition characterized by gradual cognitive impairment, including loss of synapses and nerve cells involved in learning, memory, and habit formation processes. Bone Marrow Mesenchymal Stem Cells (BM-MSCs) are multipotent cells. Because of their self-renewable, differentiation, and immunomodulatory capabilities, they are commonly used to treat many disorders. Hence, the current study intends to examine the effect of BM-MSCs transplantation on Aluminum chloride (AlCl3)-induced cognitive problems, an experimental model resembling AD’s hallmarks in rats.
Methods: The study was conducted in 2022 at The Biomedical Laboratory Faculty of Medicine, Andalas University, Indonesia. Adult male Wistar rats (three groups: negative control; no intervention+treatment with PBS; positive control: AlCl3+treatment with aqua dest; AlCl3+BM-MSCs: AlCl3+treatment with BM-MSCs, n=5 each) were treated daily with AlCl3 orally for five days. Stem cells were intraperitoneally injected into rats at a dose of 1x106 cells/rat. The same quantity of phosphate-buffered saline was given to the control group. One month after stem cell injection, the rat brain tissue was removed and placed in the film bottles that had been created. The expression of neural progenitor cell markers, including nestin and sex-determining Y-box 2 (SOX-2), was analyzed using real-time polymerase chain reaction (RT-PCR). Rats’ cognitive and functional memory were examined using Y-maze. Data were analyzed using SPSS software (version 26.0) with a one-way analysis of variance (ANOVA) test.
Results: The gene expression of nestin (29.74±0.42), SOX-2 (31.44±0.67), and percent alternation of Y-maze (67.04±2.28) increased in the AlCl3+BM-MSCs group compared to that in the positive control group. RT-PCR analysis indicated that nestin (P<0.001) and SOX-2 (P<0.001) were significantly enhanced in the AlCl3+BM-MSCs group compared to the positive control group. This group also indicated an increased percent alternation of Y-maze (P<0.001) in the AlCl3+BM-MSCs group compared to the positive control group. 
Conclusion: Due to its potential effects on cell therapy, BM-MSCs were found effective in a rat model of AD on the impairment of the rats’ behavior and increased expression of neural progenitor cell markers.

Keywords

  1. Zeng Q, Zheng M, Zhang T, He G. Hippocampal neurogenesis in the APP/PS1/nestin-GFP triple transgenic mouse model of Alzheimer’s disease. Neuroscience. 2016;314:64-74. doi: 10.1016/j.neuroscience.2015.11.054. PubMed PMID: 26639620.
  2. Aboelwafa HR, El-Kott AF, Abd-Ella EM, Yousef HN. The Possible Neuroprotective Effect of Silymarin against Aluminum Chloride-Prompted Alzheimer’s-Like Disease in Rats. Brain Sci. 2020;10. doi: 10.3390/brainsci10090628. PubMed PMID: 32932753; PubMed Central PMCID: PMCPMC7564174.
  3. Si Z, Wang X. Stem Cell Therapies in Alzheimer’s Disease: Applications for Disease Modeling. J Pharmacol Exp Ther. 2021;377:207-17. doi: 10.1124/jpet.120.000324. PubMed PMID: 33558427.
  4. Hu J, Wang X. Alzheimer’s Disease: From Pathogenesis to Mesenchymal Stem Cell Therapy - Bridging the Missing Link. Front Cell Neurosci. 2021;15:811852. doi: 10.3389/fncel.2021.811852. PubMed PMID: 35197824; PubMed Central PMCID: PMCPMC8859419.
  5. Lee M, Ban JJ, Yang S, Im W, Kim M. The exosome of adipose-derived stem cells reduces beta-amyloid pathology and apoptosis of neuronal cells derived from the transgenic mouse model of Alzheimer’s disease. Brain Res. 2018;1691:87-93. doi: 10.1016/j.brainres.2018.03.034. PubMed PMID: 29625119.
  6. Estakhri F, Reza Panjehshahin M, Tanideh N, Gheisari R, Azarpira N, Gholijani N. Efficacy of Combination Therapy with Apigenin and Synovial Membrane-Derived Mesenchymal Stem Cells on Knee Joint Osteoarthritis in a Rat Model. Iran J Med Sci. 2021;46:383-94. doi: 10.30476/IJMS.2020.83686.1301. PubMed PMID: 34539013; PubMed Central PMCID: PMCPMC8438345.
  7. Shen Z, Li X, Bao X, Wang R. Microglia-targeted stem cell therapies for Alzheimer disease: A preclinical data review. J Neurosci Res. 2017;95:2420-9. doi: 10.1002/jnr.24066. PubMed PMID: 28643422.
  8. Naaldijk Y, Jager C, Fabian C, Leovsky C, Bluher A, Rudolph L, et al. Effect of systemic transplantation of bone marrow-derived mesenchymal stem cells on neuropathology markers in APP/PS1 Alzheimer mice. Neuropathol Appl Neurobiol. 2017;43:299-314. doi: 10.1111/nan.12319. PubMed PMID: 26918424.
  9. Qin C, Lu Y, Wang K, Bai L, Shi G, Huang Y, et al. Transplantation of bone marrow mesenchymal stem cells improves cognitive deficits and alleviates neuropathology in animal models of Alzheimer’s disease: a meta-analytic review on potential mechanisms. Transl Neurodegener. 2020;9:20. doi: 10.1186/s40035-020-00199-x. PubMed PMID: 32460886; PubMed Central PMCID: PMCPMC7251864.
  10. Duncan T, Valenzuela M. Alzheimer’s disease, dementia, and stem cell therapy. Stem Cell Res Ther. 2017;8:111. doi: 10.1186/s13287-017-0567-5. PubMed PMID: 28494803; PubMed Central PMCID: PMCPMC5427593.
  11. Liu H, Zhang H, Ma Y. Molecular mechanisms of altered adult hippocampal neurogenesis in Alzheimer’s disease. Mech Ageing Dev. 2021;195:111452. doi: 10.1016/j.mad.2021.111452. PubMed PMID: 33556365.
  12. Mashhouri S, Meysam Abtahi Froushani S, Asghar Tehrani A. Non-Adherent Bone Marrow-Derived Mesenchymal Stem Cells Ameliorate Clinical Manifestations and Inflammation in an Experimental Model of Ulcerative Colitis in Rats. Iran J Med Sci. 2020;45:341-51. doi: 10.30476/ijms.2020.72514.0. PubMed PMID: 33060877; PubMed Central PMCID: PMCPMC7519406.
  13. Wei Y, Xie Z, Bi J, Zhu Z. Anti-inflammatory effects of bone marrow mesenchymal stem cells on mice with Alzheimer’s disease. Exp Ther Med. 2018;16:5015-20. doi: 10.3892/etm.2018.6857. PubMed PMID: 30542456; PubMed Central PMCID: PMCPMC6257159.
  14. Qin C, Li Y, Wang K. Functional Mechanism of Bone Marrow-Derived Mesenchymal Stem Cells in the Treatment of Animal Models with Alzheimer’s Disease: Inhibition of Neuroinflammation. J Inflamm Res. 2021;14:4761-75. doi: 10.2147/JIR.S327538. PubMed PMID: 34566422; PubMed Central PMCID: PMCPMC8456430.
  15. Sisca DY. Pengaruh pemberian mesenchymal stem cells wharton jelly terhadap ekspresi gen CALM1 dan CASP9 pada tikus alzheimer. Indonesia: Andalas University; 2021.
  16. Yu S, Hei Y, Liu W. Upregulation of seladin-1 and nestin expression in bone marrow mesenchymal stem cell transplantation via the ERK1/2 and PI3K/Akt signaling pathways in an Alzheimer’s disease model. Oncol Lett. 2018;15:7443-9. doi: 10.3892/ol.2017.7543. PubMed PMID: 29731895; PubMed Central PMCID: PMCPMC5920825.
  17. Lee C, Willerth SM, Nygaard HB. The Use of Patient-Derived Induced Pluripotent Stem Cells for Alzheimer’s Disease Modeling. Prog Neurobiol. 2020;192:101804. doi: 10.1016/j.pneurobio.2020.101804. PubMed PMID: 32464173.
  18. Khan AA, Huat TJ, Al Mutery A, El-Serafi AT, Kacem HH, Abdallah SH, et al. Significant transcriptomic changes are associated with differentiation of bone marrow-derived mesenchymal stem cells into neural progenitor-like cells in the presence of bFGF and EGF. Cell Biosci. 2020;10:126. doi: 10.1186/s13578-020-00487-z. PubMed PMID: 33133516; PubMed Central PMCID: PMCPMC7594431.
  19. Kumar K, Kumar A, Keegan RM, Deshmukh R. Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease. Biomed Pharmacother. 2018;98:297-307. doi: 10.1016/j.biopha.2017.12.053. PubMed PMID: 29274586.
  20. Ferri AL, Cavallaro M, Braida D, Di Cristofano A, Canta A, Vezzani A, et al. Sox2 deficiency causes neurodegeneration and impaired neurogenesis in the adult mouse brain. Development. 2004;131:3805-19. doi: 10.1242/dev.01204. PubMed PMID: 15240551.
  21. Sadatpoor SO, Salehi Z, Rahban D, Salimi A. Manipulated Mesenchymal Stem Cells Applications in Neurodegenerative Diseases. Int J Stem Cells. 2020;13:24-45. doi: 10.15283/ijsc19031. PubMed PMID: 32114741; PubMed Central PMCID: PMCPMC7119211.
  22. Zhao Y, Dang M, Zhang W, Lei Y, Ramesh T, Veeraraghavan VP, et al. Neuroprotective effects of Syringic acid against aluminium chloride induced oxidative stress mediated neuroinflammation in rat model of Alzheimer’s disease. Journal of Functional Foods. 2020;71:104009.
  23. Lee HJ, Lee JK, Lee H, Carter JE, Chang JW, Oh W, et al. Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through modulation of neuroinflammation. Neurobiol Aging. 2012;33:588-602. doi: 10.1016/j.neurobiolaging.2010.03.024. PubMed PMID: 20471717.
  24. Bylund M, Andersson E, Novitch BG, Muhr J. Vertebrate neurogenesis is counteracted by Sox1-3 activity. Nat Neurosci. 2003;6:1162-8. doi: 10.1038/nn1131. PubMed PMID: 14517545.
  25. Wang X, Yang G. Bone marrow mesenchymal stem cells-derived exosomes reduce Abeta deposition and improve cognitive function recovery in mice with Alzheimer’s disease by activating sphingosine kinase/sphingosine-1-phosphate signaling pathway. Cell Biol Int. 2021;45:775-84. doi: 10.1002/cbin.11522. PubMed PMID: 33300254.
  26. Guo S, Perets N, Betzer O, Ben-Shaul S, Sheinin A, Michaelevski I, et al. Intranasal Delivery of Mesenchymal Stem Cell Derived Exosomes Loaded with Phosphatase and Tensin Homolog siRNA Repairs Complete Spinal Cord Injury. ACS Nano. 2019;13:10015-28. doi: 10.1021/acsnano.9b01892. PubMed PMID: 31454225.
  27. Khan MB, Hoda MN, Vaibhav K, Giri S, Wang P, Waller JL, et al. Remote ischemic postconditioning: harnessing endogenous protection in a murine model of vascular cognitive impairment. Transl Stroke Res. 2015;6:69-77. doi: 10.1007/s12975-014-0374-6. PubMed PMID: 25351177; PubMed Central PMCID: PMCPMC4297613
  28. Koura SM, Salama M, El-Hussiny M, Khalil MEA, Lotfy A, Hassan SA, et al. Fluoxetine induces direct inhibitory effects on mesenchymal stem cellderived osteoprogenitor cells independent of serotonin concentration. Mol Med Rep. 2019;19:2611-9. doi: 10.3892/mmr.2019.9924. PubMed PMID: 30720108; PubMed Central PMCID: PMCPMC6423613.
  29. Ellis P, Fagan BM, Magness ST, Hutton S, Taranova O, Hayashi S, et al. SOX2, a persistent marker for multipotential neural stem cells derived from embryonic stem cells, the embryo or the adult. Dev Neurosci. 2004;26:148-65. doi: 10.1159/000082134. PubMed PMID: 15711057.
  30. Luo Y, Coskun V, Liang A, Yu J, Cheng L, Ge W, et al. Single-cell transcriptome analyses reveal signals to activate dormant neural stem cells. Cell. 2015;161:1175-86. doi: 10.1016/j.cell.2015.04.001. PubMed PMID: 26000486; PubMed Central PMCID: PMCPMC4851109.
  31. Zhang R, Liu Y, Yan K, Chen L, Chen XR, Li P, et al. Anti-inflammatory and immunomodulatory mechanisms of mesenchymal stem cell transplantation in experimental traumatic brain injury. J Neuroinflammation. 2013;10:106. doi: 10.1186/1742-2094-10-106. PubMed PMID: 23971414; PubMed Central PMCID: PMCPMC3765323.
  32. Cacabelos R. Pharmacogenomics of Cognitive Dysfunction and Neuropsychiatric Disorders in Dementia. Int J Mol Sci. 2020;21. doi: 10.3390/ijms21093059. PubMed PMID: 32357528; PubMed Central PMCID: PMCPMC7246738.
  33. Vizoso FJ, Eiro N, Cid S, Schneider J, Perez-Fernandez R. Mesenchymal Stem Cell Secretome: Toward Cell-Free Therapeutic Strategies in Regenerative Medicine. Int J Mol Sci. 2017;18. doi: 10.3390/ijms18091852. PubMed PMID: 28841158; PubMed Central PMCID: PMCPMC5618501.
  34. Kim DS, Lee MW, Yoo KH, Lee TH, Kim HJ, Jang IK, et al. Gene expression profiles of human adipose tissue-derived mesenchymal stem cells are modified by cell culture density. PLoS One. 2014;9:e83363. doi: 10.1371/journal.pone.0083363. PubMed PMID: 24400072; PubMed Central PMCID: PMCPMC3882209.