Wharton’ jelly mesenchymal stem cells and insulin effect on BDNF expression in CA1 and CA3 regions of rats’ hippocampus after chronic hypoxia
AbstractObjectives Brain is vulnerable to deprivation of oxygen supply during hypoxia, and therefore undergoes neurodegeneration and cognitivedysfunction. Regarded to Regenerative capacities of Wharton’s jelly mesenchymal stem cells (MSCs) and insulin at the site of injury, wewere aimed to evaluate the effect of Wharton’s jelly MSCs and insulin on degenerative consequences induced by chronic hypoxia.Methods 36 male rats were randomly divided into six groups: Control (C), Sham1-saline (Sh1), Sham2-surgery (Sh2), Hypoxia (H), Hypoxia+ Insulin (HI), Hypoxia + MSCs (HCs). Animals were exposed to hypoxic chamber (8% O2, 92% N2) for 30 days (4 hours/day) in H, HI andHCs groups. Intranasal insulin and stereotaxical MSCs in HI and HCs were used, respectively. Spatial learning and memory were analyzedusing the Morris water maze task. Brain-derived neurotrophic factor (BDNF) gene expression was studied in the hippocampus by realtime-PCR.Results BDNF had the significant depletion in HI group and magnification in HI and HCs groups comparing with C and Sh groups (P < 0.05).Insulin and MSCs improve hypoxia’s signs such as BDNF gene expression fallen and memory impairment.Conclusion In conclusion, we indicated that use of insulin hormone and MSCs as neuroprotective and stimulating factors for neurogenesis,could be beneficial in neurodegenerative damage induced by hypoxia.
2. Rybnikova E, Sitnik N, Gluschenko T, Tjulkova E, Samoilov MO. The preconditioning modified neuronal expression of apoptosis-related proteins of Bcl-2 superfamily following severe hypobaric hypoxia in rats. Brain research. 2006;1089(1):195-202.
3. Vexler ZS, Ferriero DM, editors. Molecular and biochemical mechanisms of perinatal brain injury. Seminars in neonatology; 2001: Elsevier.
4. Peterson BL, Larson J, Buffenstein R, Park TJ, Fall CP. Blunted neuronal calcium response to hypoxia in naked mole-rat hippocampus. PloS one. 2012;7(2):e31568.
5. Takada SH, dos Santos Haemmerle CA, Motta-Teixeira LC, Machado-Nils AV, Lee VY, Takase LF, et al. Neonatal anoxia in rats: hippocampal cellular and subcellular changes related to cell death and spatial memory. Neuroscience. 2015;284:247-59.
6. Chan RH, Song D, Goonawardena AV, Bough S, Sesay J, Hampson RE, et al., editors. Changes of hippocampal CA3-CA1 population nonlinear dynamics across different training sessions in rats performing a memory-dependent task. Engineering in Medicine and Biology Society (EMBC), 2010 Annual International Conference of the IEEE; 2010: IEEE.
7. Morris AM, Churchwell JC, Kesner RP, Gilbert PE. Selective lesions of the dentate gyrus produce disruptions in place learning for adjacent spatial locations. Neurobiology of learning and memory. 2012;97(3):326-31.
8. Hota SK, Hota KB, Prasad D, Ilavazhagan G, Singh SB. Oxidative-stress-induced alterations in Sp factors mediate transcriptional regulation of the NR1 subunit in hippocampus during hypoxia. Free Radical Biology and Medicine. 2010;49(2):178-91.
9. Kadar T, Arbel I, Silbermann M, Levy A. Morphological hippocampal changes during normal aging and their relation to cognitive deterioration. Cell and Animal Models in Aging and Dementia Research: Springer; 1994. p. 133-43.
10. Koh S-H, Park H-H. Neurogenesis in Stroke Recovery. Translational Stroke Research. 2017;8(1):3-13.
11. Guglielmetti C, Praet J, Rangarajan JR, Vreys R, De Vocht N, Maes F, et al. Multimodal imaging of subventricular zone neural stem/progenitor cells in the cuprizone mouse model reveals increased neurogenic potential for the olfactory bulb pathway, but no contribution to remyelination of the corpus callosum. Neuroimage. 2014;86:99-110.
12. Tang C, Zhu L, Gan W, Liang H, Li J, Zhang J, et al. Distributed Features of Vimentin-Containing Neural Precursor Cells in Olfactory Bulb of SOD1G93A Transgenic Mice: a Study about Resource of Endogenous Neural Stem Cells. International journal of biological sciences. 2016;12(12):1405.
13. Sabbaghziarani F, Mortezaee K, Akbari M, Soleimani M, Moini A, Ataeinejad N, et al. Retinoic acid-pretreated Wharton’s jelly mesenchymal stem cells in combination with triiodothyronine improve expression of neurotrophic factors in the subventricular zone of the rat ischemic brain injury. Metabolic brain disease. 2017;32(1):185-93.
14. Goldberg NR, Caesar J, Park A, Sedgh S, Finogenov G, Masliah E, et al. Neural stem cells rescue cognitive and motor dysfunction in a transgenic model of dementia with Lewy bodies through a BDNF-dependent mechanism. Stem Cell Reports. 2015;5(5):791-804.
15. Obernier K, Tong CK, Alvarez-Buylla A. Restricted nature of adult neural stem cells: re-evaluation of their potential for brain repair. Frontiers in neuroscience. 2014;8.
16. Martins LF, Costa RO, Pedro JR, Aguiar P, Serra SC, Teixeira FG, et al. Mesenchymal stem cells secretome-induced axonal outgrowth is mediated by BDNF. Scientific Reports. 2017;7.
17. Konala VBR, Mamidi MK, Bhonde R, Das AK, Pochampally R, Pal R. The current landscape of the mesenchymal stromal cell secretome: a new paradigm for cell-free regeneration. Cytotherapy. 2016;18(1):13-24.
18. Agis‐Balboa RC, Arcos‐Diaz D, Wittnam J, Govindarajan N, Blom K, Burkhardt S, et al. A hippocampal insulin‐growth factor 2 pathway regulates the extinction of fear memories. The EMBO journal. 2011;30(19):4071-83.
19. Erickson RI, Paucar AA, Jackson RL, Visnyei K, Kornblum H. Roles of insulin and transferrin in neural progenitor survival and proliferation. Journal of neuroscience research. 2008;86(8):1884-94.
20. Ziegler AN, Levison SW, Wood TL. Insulin and IGF receptor signalling in neural-stem-cell homeostasis. Nature Reviews Endocrinology. 2015;11(3):161-70.
21. Rice JE, Vannucci RC, Brierley JB. The influence of immaturity on hypoxic‐ischemic brain damage in the rat. Annals of neurology. 1981;9(2):131-41.
22. Hassanzadeh G, Fallahi Z, Khanmohammadi M, Elmizadeh H, Sharifzadeh M, Mahakizadeh S, et al. Effect of Magnetic Tacrine-Loaded Chitosan Nanoparticles on Spatial Learning, Memory, Amyloid Precursor Protein and Seladin-1 Expression in the Hippocampus of Streptozotocin-Exposed Rats. International Clinical Neuroscience Journal. 2016;3(1):25-31.
23. El Falougy H, Kubikova E, Benuska J. The microscopical structure of the hippocampus in the rat. Bratislavske lekarske listy. 2008;109(3):106.
24. Vetrovoi O, Rybnikova E, Glushchenko T, Samoilov M. Effects of hypoxic postconditioning on the expression of antiapoptotic protein Bcl-2 and neurotrophin BDNF in hippocampal field CA1 in rats subjected to severe hypoxia. Neuroscience and Behavioral Physiology. 2015;45(4):367.
25. Hota KB, Hota SK, Srivastava RB, Singh SB. Neuroglobin regulates hypoxic response of neuronal cells through Hif-1 α-and Nrf2-mediated mechanism. Journal of Cerebral Blood Flow & Metabolism. 2012;32(6):1046-60.
26. Taran R, Mamidi MK, Singh G, Dutta S, Parhar IS, John JP, et al. In vitro and in vivo neurogenic potential of mesenchymal stem cells isolated from different sources. Journal of biosciences. 2014;39(1):157-69.
27. Messerli M, Wagner A, Sager R, Mueller M, Baumann M, Surbek DV, et al. Stem cells from umbilical cord Wharton’s jelly from preterm birth have neuroglial differentiation potential. Reproductive sciences. 2013;20(12):1455-64.
28. Giannakopoulou A, Lyras GA, Grigoriadis N. Long‐term effects of autoimmune CNS inflammation on adult hippocampal neurogenesis. Journal of neuroscience research. 2017;95(7):1446-58.
29. Tobin MK, Bonds JA, Minshall RD, Pelligrino DA, Testai FD, Lazarov O. Neurogenesis and inflammation after ischemic stroke: what is known and where we go from here. Journal of Cerebral Blood Flow & Metabolism. 2014;34(10):1573-84.
30. Fuentealba LC, Rompani SB, Parraguez JI, Obernier K, Romero R, Cepko CL, et al. Embryonic origin of postnatal neural stem cells. Cell. 2015;161(7):1644-55.
31. Linnarsson S, Willson CA, Ernfors P. Cell death in regenerating populations of neurons in BDNF mutant mice. Molecular Brain Research. 2000;75(1):61-9.
32. Gao LR, Zhang NK, Ding QA, Chen HY, Hu X, Jiang S, et al. Common expression of stemness molecular markers and early cardiac transcription factors in human Wharton’s jelly-derived mesenchymal stem cells and embryonic stem cells. Cell transplantation. 2013;22(10):1883-900.
33. Hsieh J-Y, Wang H-W, Chang S-J, Liao K-H, Lee I-H, Lin W-S, et al. Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis. PloS one. 2013;8(8):e72604.
34. Shirayama Y, Yang C, Zhang J-c, Ren Q, Yao W, Hashimoto K. Alterations in brain-derived neurotrophic factor (BDNF) and its precursor proBDNF in the brain regions of a learned helplessness rat model and the antidepressant effects of a TrkB agonist and antagonist. European Neuropsychopharmacology. 2015;25(12):2449-58.
35. Sun J, Qu Y, He H, Fan X, Qin Y, Mao W, et al. Protective effect of polydatin on learning and memory impairments in neonatal rats with hypoxic‑ischemic brain injury by up‑regulating brain‑derived neurotrophic factor. Molecular medicine reports. 2014;10(6):3047-51.
36. Brewer G, Torricelli J, Evege E, Price P. Optimized survival of hippocampal neurons in B27‐supplemented neurobasal™, a new serum‐free medium combination. Journal of neuroscience research. 1993;35(5):567-76.
37. O’Kusky J, Ye P. Neurodevelopmental effects of insulin-like growth factor signaling. Frontiers in neuroendocrinology. 2012;33(3):230-51.
38. LaFever L, Drummond-Barbosa D. Direct control of germline stem cell division and cyst growth by neural insulin in Drosophila. Science. 2005;309(5737):1071-3.
39. Reger M, Watson G, Green P, Wilkinson CW, Baker LD, Cholerton B, et al. Intranasal insulin improves cognition and modulates β-amyloid in early AD. Neurology. 2008;70(6):440-8.
40. Gratuze M, Julien J, Petry FR, Morin F, Planel E. Insulin deprivation induces PP2A inhibition and tau hyperphosphorylation in hTau mice, a model of Alzheimer’s disease-like tau pathology. Scientific Reports. 2017;7.
41. Neves FS, Marques PT, Barros‑Aragão F, Nunes JB, Venancio AM, Cozachenco D, et al. Brain-Defective Insulin Signaling Is Associated to Late Cognitive Impairment in Post-Septic Mice. Molecular Neurobiology. 2016:1-10.
42. Kernie SG, Parent JM. Forebrain neurogenesis after focal Ischemic and traumatic brain injury. Neurobiology of disease. 2010;37(2):267-74.