Abstract
Chitosan nanoparticles and valproic acid are demonstrated as the protective agents in the treatment of spinal cord injury (SCI). However, the effects of valproic acid-labeled chitosan nanoparticles (VA-CN) on endogenous spinal cord neural stem cells (NSCs) following SCI and the underlying mechanisms involved remain to be elucidated. In this study, the VA-CN was constructed and the effects of VA-CN on NSCs were assessed in a rat model of SCI. We found VA-CN treatment promoted recovery of the tissue and locomotive function following SCI. Moreover, administration of VA-CN significantly enhanced neural stem cell proliferation and the expression levels of neurotrophic factors following SCI. Furthermore, administration of VA-CN led to a decrease in the number of microglia following SCI. In addition, VA-CN treatment significantly increased the Tuj 1- positive cells in the spinal cord of the SCI rats, suggesting that VA-CN could enhance the differentiation of NSCs following SCI. In conclusion, these results demonstrated that VA-CN could improve the functional and histological recovery through promoting the proliferation and differentiation of NSCs following SCI, which would provide a newly potential therapeutic manner for the treatment of SCI.
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References
Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W (2017) Cell transplantation therapy for spinal cord injury. Nat Neurosci 20(5):637–647. https://doi.org/10.1038/nn.4541
Baniasadi H, Ramazani SAA, Mashayekhan S (2015) Fabrication and characterization of conductive chitosan/gelatin-based scaffolds for nerve tissue engineering. Int J Biol Macromol 74:360–366. https://doi.org/10.1016/j.ijbiomac.2014.12.014
Camarero G, Leon Y, Gorospe I, De Pablo F, Alsina B, Giraldez F, Varela-Nieto I (2003) Insulin-like growth factor 1 is required for survival of transit-amplifying neuroblasts and differentiation of otic neurons. Dev Biol 262(2):242–253. https://doi.org/10.1016/s0012-1606(03)00387-7
Chen S, Ye J, Chen X, Shi J, Wu W, Lin W, Li S (2018) Valproic acid attenuates traumatic spinal cord injury-induced inflammation via STAT1 and NF-kappaB pathway dependent of HDAC3. J Neuroinflammation 15(1):150. https://doi.org/10.1186/s12974-018-1193-6
Chandrasekaran A, Avci HX, Ochalek A, Rosingh LN, Molnar K, Laszlo L, Dinnyes A (2017) Comparison of 2D and 3D neural induction methods for the generation of neural progenitor cells from human induced pluripotent stem cells. Stem Cell Res 25:139–151. https://doi.org/10.1016/j.scr.2017.10.010
Chen B, Bohnert D, Borgens RB, Cho Y (2013) Pushing the science forward: chitosan nanoparticles and functional repair of CNS tissue after spinal cord injury. J Biol Eng 7:15. https://doi.org/10.1186/1754-1611-7-15
Chu T, Zhou H, Wang T, Lu L, Li F, Liu B, Feng S (2015) In vitro characteristics of valproic acid and all-trans-retinoic acid and their combined use in promoting neuronal differentiation while suppressing astrocytic differentiation in neural stem cells. Brain Res 1596:31–47. https://doi.org/10.1016/j.brainres.2014.11.029
Cusimano M, Biziato D, Brambilla E, Donega M, Alfaro-Cervello C, Snider S, Pluchino S (2012) Transplanted neural stem/precursor cells instruct phagocytes and reduce secondary tissue damage in the injured spinal cord. Brain 135(Pt 2):447–460. https://doi.org/10.1093/brain/awr339
Cusimano M, Brambilla E, Capotondo A, De Feo D, Tomasso A, Comi G, Martino G (2018) Selective killing of spinal cord neural stem cells impairs locomotor recovery in a mouse model of spinal cord injury. J Neuroinflammation 15(1):58. https://doi.org/10.1186/s12974-018-1085-9
Du JP, Fan Y, Zhang JN, Liu JJ, Meng YB, Hao DJ (2019) Early versus delayed decompression for traumatic cervical spinal cord injury: application of the AOSpine subaxial cervical spinal injury classification system to guide surgical timing. Eur Spine J. https://doi.org/10.1007/s00586-019-05959-6
Eckert MJ, Martin MJ (2017) Trauma: Spinal Cord Injury. Surg Clin North Am 97(5):1031–1045. https://doi.org/10.1016/j.suc.2017.06.008
Farzanehfar P, Horne MK, Aumann TD (2017) Can Valproic Acid Regulate Neurogenesis from Nestin+ Cells in the Adult Midbrain? Neurochem Res 42(8):2127–2134. https://doi.org/10.1007/s11064-017-2259-z
Forbes LH, Andrews MR (2019) Grafted Human iPSC-Derived Neural Progenitor Cells Express Integrins and Extend Long-Distance Axons Within the Developing Corticospinal Tract. Front Cell Neurosci 13:26. https://doi.org/10.3389/fncel.2019.00026
Galatro TF, Holtman IR, Lerario AM, Vainchtein ID, Brouwer N, Sola PR, Veras MM, Pereira TF, Leite REP, Möller T, Wes PD, Sogayar MC, Laman JD, den Dunnen W, Pasqualucci CA, Oba-Shinjo SM, Boddeke EWGM, Marie SKN, Eggen BJL (2017) Transcriptomic analysis of purified human cortical microglia reveals age-associated changes. Nat Neurosci 20(8):1162–1171. https://doi.org/10.1038/nn.4597
Gao J, Bai H, Li Q, Li J, Wan F, Tian M, Li Y, Song Y, Zhang J, Si Y (2018) In vitro investigation of the mechanism underlying the effect of ginsenoside on the proliferation and differentiation of neural stem cells subjected to oxygen-glucose deprivation/reperfusion. Int J Mol Med 41(1):353–363. https://doi.org/10.3892/ijmm.2017.3253
Gregoire CA, Goldenstein BL, Floriddia EM, Barnabe-Heider F, Fernandes KJ (2015) Endogenous neural stem cell responses to stroke and spinal cord injury. Glia 63(8):1469–1482. https://doi.org/10.1002/glia.22851
Gonzalez R, Garitaonandia I, Poustovoitov M, Abramihina T, McEntire C, Culp B, Kern RA (2016) Neural Stem Cells Derived from Human Parthenogenetic Stem Cells Engraft and Promote Recovery in a Nonhuman Primate Model of Parkinson’s Disease. Cell Transplant 25(11):1945–1966. https://doi.org/10.3727/096368916X691682
Hamilton LK, Fernandes KJL (2018) Neural stem cells and adult brain fatty acid metabolism: Lessons from the 3xTg model of Alzheimer’s disease. Biol Cell 110(1):6–25. https://doi.org/10.1111/boc.201700037
Hodgetts SI, Harvey AR (2017) Neurotrophic Factors Used to Treat Spinal Cord Injury. Vitam Horm 104:405–457. https://doi.org/10.1016/bs.vh.2016.11.007
Hsieh J, Nakashima K, Kuwabara T, Mejia E, Gage FH (2004) Histone deacetylase inhibition-mediated neuronal differentiation of multipotent adult neural progenitor cells. Proc Natl Acad Sci U S A 101(47):16659–16664. https://doi.org/10.1073/pnas.0407643101
Jazayeri SB, Beygi S, Shokraneh F, Hagen EM, Rahimi-Movaghar V (2015) Incidence of traumatic spinal cord injury worldwide: a systematic review. Eur Spine J 24(5):905–918. https://doi.org/10.1007/s00586-014-3424-6
Keller L, Regiel-Futyra A, Gimeno M, Eap S, Mendoza G, Andreu V, Benkirane-Jessel N (2017) Chitosan-based nanocomposites for the repair of bone defects. Nanomedicine 13(7):2231–2240. https://doi.org/10.1016/j.nano.2017.06.007
Khan TI, Hemalatha S, Waseem M (2020) Promising role of nano-encapsulated drugs for spinal cord injury. Mol Neurobiol 57(4):1978–1985. https://doi.org/10.1007/s12035-019-01862-9
Kumamaru H, Lu P, Rosenzweig ES, Kadoya K, Tuszynski MH (2019) Regenerating Corticospinal Axons Innervate Phenotypically Appropriate Neurons within Neural Stem Cell Grafts. Cell Rep 26(9):2329–2339. https://doi.org/10.1016/j.celrep.2019.01.099
Kumamaru H, Saiwai H, Kubota K, Kobayakawa K, Yokota K, Ohkawa Y, Okada S (2013) Therapeutic activities of engrafted neural stem/precursor cells are not dormant in the chronically injured spinal cord. Stem Cells 31(8):1535–1547. https://doi.org/10.1002/stem.1404
Lee KB, Choi JH, Byun K, Chung KH, Ahn JH, Jeong GB, Lee B (2012) Recovery of CNS pathway innervating the sciatic nerve following transplantation of human neural stem cells in rat spinal cord injury. Cell Mol Neurobiol 32(1):149–157. https://doi.org/10.1007/s10571-011-9745-7
Li L, Xiao B, Mu J, Zhang Y, Zhang C, Cao H, Chen R, Patra HK, Yang B, Feng S, Tabata Y, Slater NKH, Tang J, Shen Y, Gao J (2019) A MnO2 nanoparticle-dotted hydrogel promotes spinal cord repair via regulating reactive oxygen species microenvironment and synergizing with mesenchymal stem cells. ACS Nano 13(12):14283–14293. https://doi.org/10.1021/acsnano.9b07598
Li X, Zhao Y, Cheng S, Han S, Shu M, Chen B, Dai J (2017) Cetuximab modified collagen scaffold directs neurogenesis of injury-activated endogenous neural stem cells for acute spinal cord injury repair. Biomaterials 137:73–86. https://doi.org/10.1016/j.biomaterials.2017.05.027
Lu WH, Wang CY, Chen PS, Wang JW, Chuang DM, Yang CS, Tzeng SF (2013) Valproic acid attenuates microgliosis in injured spinal cord and purinergic P2X4 receptor expression in activated microglia. J Neurosci Res 91(5):694–705. https://doi.org/10.1002/jnr.23200
Lu P, Kadoya K, Tuszynski MH (2014) Axonal growth and connectivity from neural stem cell grafts in models of spinal cord injury. Curr Opin Neurobiol 27:103–109. https://doi.org/10.1016/j.conb.2014.03.010
Lu P, Wang Y, Graham L, McHale K, Gao M, Wu D, Tuszynski MH (2012) Long-distance growth and connectivity of neural stem cells after severe spinal cord injury. Cell 150(6):1264–1273. https://doi.org/10.1016/j.cell.2012.08.020
Marsh SE, Blurton-Jones M (2017) Neural stem cell therapy for neurodegenerative disorders: The role of neurotrophic support. Neurochem Int 106:94–100. https://doi.org/10.1016/j.neuint.2017.02.006
Mittnacht U, Hartmann H, Hein S, Oliveira H, Dong M, Pego AP, Schlosshauer B (2010) Chitosan/siRNA nanoparticles biofunctionalize nerve implants and enable neurite outgrowth. Nano Lett 10(10):3933–3939. https://doi.org/10.1021/nl1016909
Mourelo FM, Salvador de la BS, Montoto MA, Ferreiro VME, & Galeiras VR (2017) Update on traumatic acute spinal cord injury. Part 2. Med Intensiva 41(5):306–315. https://doi.org/10.1016/j.medin.2016.10.014
Nguyen LH, Gao M, Lin J, Wu W, Wang J, Chew SY (2017) Three-dimensional aligned nanofibers-hydrogel scaffold for controlled non-viral drug/gene delivery to direct axon regeneration in spinal cord injury treatment. Sci Rep 7:42212. https://doi.org/10.1038/srep42212
Ottoboni L, Merlini A, Martino G (2017) Neural Stem Cell Plasticity: Advantages in Therapy for the Injured Central Nervous System. Front Cell Dev Biol 5:52. https://doi.org/10.3389/fcell.2017.00052
Pandamooz S, Salehi MS, Nabiuni M, Dargahi L (2017) Valproic acid preserves motoneurons following contusion in organotypic spinal cord slice culture. J Spinal Cord Med 40(1):100–106. https://doi.org/10.1080/10790268.2016.1213518
Penas C, Verdu E, Asensio-Pinilla E, Guzman-Lenis MS, Herrando-Grabulosa M, Navarro X, Casas C (2011) Valproate reduces CHOP levels and preserves oligodendrocytes and axons after spinal cord injury. Neuroscience 178:33–44. https://doi.org/10.1016/j.neuroscience.2011.01.012
Rauch MF, Hynes SR, Bertram J, Redmond A, Robinson R, Williams C, Lavik EB (2009) Engineering angiogenesis following spinal cord injury: a coculture of neural progenitor and endothelial cells in a degradable polymer implant leads to an increase in vessel density and formation of the blood-spinal cord barrier. Eur J Neurosci 29(1):132–145. https://doi.org/10.1111/j.1460-9568.2008.06567.x
Rouanet C, Reges D, Rocha E, Gagliardi V, Silva GS (2017) Traumatic spinal cord injury: current concepts and treatment update. Arq Neuropsiquiatr 75(6):387–393. https://doi.org/10.1590/0004-282X20170048
Shin DC, Ha KY, Kim YH, Kim JW, Cho YK, Kim SI (2018) Induction of Endogenous Neural Stem Cells By Extracorporeal Shock Waves After Spinal Cord Injury. Spine Phila Pa 43(4):E200–E207. https://doi.org/10.1097/BRS.0000000000002302
Sinden JD, Hicks C, Stroemer P, Vishnubhatla I, Corteling R (2017) Human Neural Stem Cell Therapy for Chronic Ischemic Stroke: Charting Progress from Laboratory to Patients. Stem Cells Dev 26(13):933–947. https://doi.org/10.1089/scd.2017.0009
Stenudd M, Sabelstrom H, Frisen J (2015) Role of endogenous neural stem cells in spinal cord injury and repair. JAMA Neurol 72(2):235–237. https://doi.org/10.1001/jamaneurol.2014.2927
Teng YD, Liao WL, Choi H, Konya D, Sabharwal S, Langer R, Frontera WR (2006) Physical activity-mediated functional recovery after spinal cord injury: potential roles of neural stem cells. Regen Med 1(6):763–776. https://doi.org/10.2217/17460751.1.6.763
Tomita T, Akimoto J, Haraoka J, Kudo M (2014) Clinicopathological significance of expression of nestin, a neural stem/progenitor cell marker, in human glioma tissue. Brain Tumor Pathol 31(3):162–171. https://doi.org/10.1007/s10014-013-0169-6
Wang D, Wang K, Liu Z, Wang Z, Wu H (2020) Valproic acid-labeled chitosan nanoparticles promote recovery of neuronal injury after spinal cord injury. Aging (Albany NY) 12(10):8953–8967. https://doi.org/10.18632/aging.103125
Wu W, Lee SY, Wu X, Tyler JY, Wang H, Ouyang Z, Park K, Xu XM, Cheng JX (2014) Neuroprotective ferulic acid (FA)-glycol chitosan (GC) nanoparticles for functional restoration of traumatically injured spinal cord. Biomaterials 35(7):2355–2364. https://doi.org/10.1016/j.biomaterials.2013.11.074
Xu L, Xu CJ, Lu HZ, Wang YX, Li Y, Lu PH (2010) Long-term fate of allogeneic neural stem cells following transplantation into injured spinal cord. Stem Cell Rev 6(1):121–136. https://doi.org/10.1007/s12015-009-9104-y
Yan S, Li P, Wang Y, Yu W, Qin A, Liu M, Li W (2016) Nestin regulates neural stem cell migration via controlling the cell contractility. Int J Biochem Cell Biol 78:349–360. https://doi.org/10.1016/j.biocel.2016.07.034
Yousefifard M, Rahimi-Movaghar V, Nasirinezhad F, Baikpour M, Safari S, Saadat S, Hosseini M (2016) Neural stem/progenitor cell transplantation for spinal cord injury treatment; A systematic review and meta-analysis. Neuroscience 322:377–397. https://doi.org/10.1016/j.neuroscience.2016.02.034
Zhang LQ, Zhang WM, Deng L, Xu ZX, Lan WB, Lin JH (2018) Transplantation of a Peripheral Nerve with Neural Stem Cells Plus Lithium Chloride Injection Promote the Recovery of Rat Spinal Cord Injury. Cell Transplant 27(3):471–484. https://doi.org/10.1177/0963689717752945
Zi-Wei L, Li CW, Wang Q, Shi SJ, Hu M, Zhang Q, Lu LC (2017) The Cellular and Molecular Mechanisms Underlying Silver Nanoparticle/Chitosan Oligosaccharide/Poly(vinyl alcohol) Nanofiber-Mediated Wound Healing. J Biomed Nanotechnol 13(1):17–34
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This work was supported by Natural Science Foundation of Beijing (NSF) grant (KZ201910025028).
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Wang, D., Wang, K., Liu, Z. et al. Valproic Acid Labeled Chitosan Nanoparticles Promote the Proliferation and Differentiation of Neural Stem Cells After Spinal Cord Injury. Neurotox Res 39, 456–466 (2021). https://doi.org/10.1007/s12640-020-00304-y
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DOI: https://doi.org/10.1007/s12640-020-00304-y