Login Register Cart 0
Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Editor-in-Chief

ISSN (Print): 1871-5273
ISSN (Online): 1996-3181

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Early Expression of Neuronal Dopaminergic Markers in a Parkinson’s Disease Model in Rats Implanted with Enteric Stem Cells (ENSCs)

Author(s): Carmen Parra-Cid*, Eduardo Orozco-Castillo, Julieta García-López, Elena Contreras-Figueroa, Laura E. Ramos-Languren, Clemente Ibarra, Alfonso Carreón-Rodríguez, Michael Aschner, Mina Königsberg and Abel Santamaría*

Volume 19, Issue 2, 2020

Page: [148 - 162] Pages: 15

DOI: 10.2174/1871527319666200417123948

Price: $65

Abstract

Background: Parkinson’s Disease (PD) is a common neurodegenerative disorder affecting the dopaminergic (DAergic) system. Replacement therapy is a promising alternative aimed at reconstructing the cytoarchitecture of affected brain regions in PD. Experimental approaches, such as the replacement of DAergic neurons with cells obtained from the Enteric Nervous System (ENS) has yet to be explored.

Objective: To establish and characterize a cell replacement strategy with ENS Cells (ENSCs) in a PD model in rats.

Methods: Since ENSCs can develop mature DAergic phenotypes, here we cultured undifferentiated cells from the myenteric plexus of newborn rats, establishing that they exhibit multipotential characteristics. These cells were characterized and further implanted in the Substantia nigra pars compacta (SNpc) of adult rats previously lesioned by a retrograde degenerative model produced by intrastriatal injection of 6-Hydroxydopamine (6-OHDA). DAergic markers were assessed in implants to validate their viability and possible differentiation once implanted.

Results: Cell cultures were viable, exhibited stem cell features and remained partially undifferentiated until the time of implant. The retrograde lesion induced by 6-OHDA produced DAergic denervation, reducing the number of fibers and cells in the SNpc. Implantation of ENSCs in the SNpc of 6-OHDAlesioned rats was tracked after 5 and 10 days post-implant. During that time, the implant increased selective neuronal and DAergic markers, Including Microtubule-Associated Protein 2 (MAP-2), Dopamine Transporter (DAT), and Tyrosine Hydroxylase (TH).

Conclusion: Our novel results suggest that ENSCs possess a differentiating, proliferative and restorative potential that may offer therapeutic modalities to attenuate neurodegenerative events with the inherent demise of DAergic neurons.

Keywords: Replacement therapy, stem cells, 6-hydroxydopamine, enteric nervous system, Parkinson’s disease, dopaminergic markers.

« Previous Next »
Graphical Abstract

[1]
Nakata Y, Yasuda T, Mochizuki H. Recent progress in gene therapy for Parkinson’s disease. Curr Mol Med 2012; 12(10): 1311-8.
[http://dx.doi.org/10.2174/156652412803833580] [PMID: 22834832]
[2]
Meder D, Herz DM, Rowe JB, Lehéricy S, Siebner HR. The role of dopamine in the brain - lessons learned from Parkinson’s disease. Neuroimage 2019; 190: 79-93.
[http://dx.doi.org/10.1016/j.neuroimage.2018.11.021] [PMID: 30465864]
[3]
Borah A, Mohanakumar KP. L-DOPA induced-endogenous 6-hydroxydopamine is the cause of aggravated dopaminergic neurodegeneration in Parkinson’s disease patients. Med Hypotheses 2012; 79(2): 271-3.
[http://dx.doi.org/10.1016/j.mehy.2012.05.008] [PMID: 22641021]
[4]
Ungerstedt U. 6-Hydroxy-dopamine induced degeneration of central monoamine neurons. Eur J Pharmacol 1968; 5(1): 107-10.
[http://dx.doi.org/10.1016/0014-2999(68)90164-7] [PMID: 5718510]
[5]
Cenci MA, Whishaw IQ, Schallert T. Animal models of neurological deficits: how relevant is the rat? Nat Rev Neurosci 2002; 3(7): 574-9.
[http://dx.doi.org/10.1038/nrn877] [PMID: 12094213]
[6]
Blesa J, Phani S, Jackson-Lewis V, Przedborski S. Classic and new animal models of Parkinson’s disease. J Biomed Biotechnol 2012; 2012: 845618
[http://dx.doi.org/10.1155/2012/845618] [PMID: 22536024]
[7]
Cheon SM, Chan L, Chan DK, Kim JW. Genetics of Parkinson’s disease - a clinical perspective. J Mov Disord 2012; 5(2): 33-41.
[http://dx.doi.org/10.14802/jmd.12009] [PMID: 24868412]
[8]
Ma Y, Tang C, Chaly T, et al. Dopamine cell implantation in Parkinson’s disease: long-term clinical and (18)F-FDOPA PET outcomes. J Nucl Med 2010; 51(1): 7-15.
[http://dx.doi.org/10.2967/jnumed.109.066811] [PMID: 20008998]
[9]
Politis M, Wu K, Loane C, et al. Serotonergic neurons mediate dyskinesia side effects in Parkinson’s patients with neural transplants. Sci Transl Med 2010; 2(38): 38ra46
[http://dx.doi.org/10.1126/scitranslmed.3000976] [PMID: 20592420]
[10]
Bergmann O, Spalding KL, Frisén J. Adult neurogenesis in humans. Cold Spring Harb Perspect Biol 2015; 7(7): a018994
[http://dx.doi.org/10.1101/cshperspect.a018994] [PMID: 26134318]
[11]
Schäfer KH, Van Ginneken C, Copray S. Plasticity and neural stem cells in the enteric nervous system. Anat Rec (Hoboken) 2009; 292(12): 1940-52.
[http://dx.doi.org/10.1002/ar.21033] [PMID: 19943347]
[12]
Azan G, Low WC, Wendelschafer-Crabb G, Ikramuddin S, Kennedy WR. Evidence for neural progenitor cells in the human adult enteric nervous system. Cell Tissue Res 2011; 344(2): 217-25.
[http://dx.doi.org/10.1007/s00441-011-1130-9] [PMID: 21369860]
[13]
Joseph NM, He S, Quintana E, Kim YG, Núñez G, Morrison SJ. Enteric glia are multipotent in culture but primarily form glia in the adult rodent gut. J Clin Invest 2011; 121(9): 3398-411.
[http://dx.doi.org/10.1172/JCI58186] [PMID: 21865643]
[14]
Mayani H. A glance into somatic stem cell biology: basic principles, new concepts, and clinical relevance. Arch Med Res 2003; 34(1): 3-15.
[http://dx.doi.org/10.1016/S0188-4409(02)00450-2] [PMID: 12604368]
[15]
P M, S H, R M, M G, W S K. Adult mesenchymal stem cells and cell surface characterization - a systematic review of the literature. Open Orthop J 2011; 5(Suppl. 2): 253-60.
[http://dx.doi.org/10.2174/1874325001105010253] [PMID: 21966340]
[16]
Elliott AM, Elliott KA, Kammesheidt A. Array-comparative genomic hybridization characterization of human pluripotent stem cells. Methods Mol Biol 2012; 873: 261-7.
[http://dx.doi.org/10.1007/978-1-61779-794-1_17] [PMID: 22528361]
[17]
Silva-Vargas V, Crouch EE, Doetsch F. Adult neural stem cells and their niche: a dynamic duo during homeostasis, regeneration, and aging. Curr Opin Neurobiol 2013; 23(6): 935-42.
[http://dx.doi.org/10.1016/j.conb.2013.09.004] [PMID: 24090877]
[18]
Hotta R, Stamp LA, Foong JP, et al. Transplanted progenitors generate functional enteric neurons in the postnatal colon. J Clin Invest 2013; 123(3): 1182-91.
[http://dx.doi.org/10.1172/JCI65963] [PMID: 23454768]
[19]
Hagl CI, Heumüller-Klug S, Wink E, Wessel L, Schäfer KH. The human gastrointestinal tract, a potential autologous neural stem cell source. PLoS One 2013; 8(9): e72948
[http://dx.doi.org/10.1371/journal.pone.0072948] [PMID: 24023797]
[20]
Seaberg RM, Smukler SR, Kieffer TJ, et al. Clonal identification of multipotent precursors from adult mouse pancreas that generate neural and pancreatic lineages. Nat Biotechnol 2004; 22(9): 1115-24.
[http://dx.doi.org/10.1038/nbt1004] [PMID: 15322557]
[21]
Smukler SR, Arntfield ME, Razavi R, et al. The adult mouse and human pancreas contain rare multipotent stem cells that express insulin. Cell Stem Cell 2011; 8(3): 281-93.
[http://dx.doi.org/10.1016/j.stem.2011.01.015] [PMID: 21362568]
[22]
Jiang Y, Jahagirdar BN, Reinhardt RL, et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418(6893): 41-9.
[http://dx.doi.org/10.1038/nature00870] [PMID: 12077603]
[23]
Herzog EL, Chai L, Krause DS. Plasticity of marrow-derived stem cells. Blood 2003; 102(10): 3483-93.
[http://dx.doi.org/10.1182/blood-2003-05-1664] [PMID: 12893756]
[24]
Avetisyan M, Schill EM, Heuckeroth RO. Building a second brain in the bowel. J Clin Invest 2015; 125(3): 899-907.
[http://dx.doi.org/10.1172/JCI76307] [PMID: 25664848]
[25]
Sanchez-Ramos J, Song S, Cardozo-Pelaez F, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000; 164(2): 247-56.
[http://dx.doi.org/10.1006/exnr.2000.7389] [PMID: 10915564]
[26]
Zuk PA, Zhu M, Ashjian P, et al. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13(12): 4279-95.
[http://dx.doi.org/10.1091/mbc.e02-02-0105] [PMID: 12475952]
[27]
Parra-Cid C, García-López J, García E, Ibarra C. An enteric nervous system progenitor cell implant promotes a behavioral and neurochemical improvement in rats with a 6-OHDA-induced lesion. Neurotoxicol Teratol 2014; 43: 45-50.
[http://dx.doi.org/10.1016/j.ntt.2014.03.005] [PMID: 24686028]
[28]
Belkind-Gerson J, Carreon-Rodríguez A, Benedict LA, et al. Nestin-expressing cells in the gut give rise to enteric neurons and glial cells. Neurogastroenterol Motil 2013; 25(1): 61-9.e7.
[http://dx.doi.org/10.1111/nmo.12015] [PMID: 22998406]
[29]
Suárez-Rodríguez R, Belkind-Gerson J. Cultured nestin-positive cells from postnatal mouse small bowel differentiate ex vivo into neurons, glia, and smooth muscle. Stem Cells 2004; 22(7): 1373-85.
[http://dx.doi.org/10.1634/stemcells.2003-0049] [PMID: 15579654]
[30]
Paxinos G, Watson C. The rat brain in stereotaxic coordinates. 6th ed. London: Academic Press 1998; p. 35.
[31]
Sauer H, Oertel WH. Progressive degeneration of nigrostriatal dopamine neurons following intrastriatal terminal lesions with 6-hydroxydopamine: a combined retrograde tracing and immunocytochemical study in the rat. Neuroscience 1994; 59(2): 401-15.
[http://dx.doi.org/10.1016/0306-4522(94)90605-X] [PMID: 7516500]
[32]
Przedborski S, Levivier M, Jiang H, et al. Dose-dependent lesions of the dopaminergic nigrostriatal pathway induced by intrastriatal injection of 6-hydroxydopamine. Neuroscience 1995; 67(3): 631-47.
[http://dx.doi.org/10.1016/0306-4522(95)00066-R] [PMID: 7675192]
[33]
Young HM, Bergner AJ, Müller T. Acquisition of neuronal and glial markers by neural crest-derived cells in the mouse intestine. J Comp Neurol 2003; 456(1): 1-11.
[http://dx.doi.org/10.1002/cne.10448] [PMID: 12508309]
[34]
Liu MT, Kuan YH, Wang J, Hen R, Gershon MD. 5-HT4 receptor-mediated neuroprotection and neurogenesis in the enteric nervous system of adult mice. J Neurosci 2009; 29(31): 9683-99.
[http://dx.doi.org/10.1523/JNEUROSCI.1145-09.2009] [PMID: 19657021]
[35]
Kempermann G, Jessberger S, Steiner B, Kronenberg G. Milestones of neuronal development in the adult hippocampus. Trends Neurosci 2004; 27(8): 447-52.
[http://dx.doi.org/10.1016/j.tins.2004.05.013] [PMID: 15271491]
[36]
Chauhan NB, Siegel GJ, Lee JM. Depletion of glial cell line-derived neurotrophic factor in substantia nigra neurons of Parkinson’s disease brain. J Chem Neuroanat 2001; 21(4): 277-88.
[http://dx.doi.org/10.1016/S0891-0618(01)00115-6] [PMID: 11429269]
[37]
Nemoto C, Hida T, Arai R. Calretinin and calbindin-D28k in dopaminergic neurons of the rat midbrain: a triple-labeling immunohistochemical study. Brain Res 1999; 846(1): 129-36.
[http://dx.doi.org/10.1016/S0006-8993(99)01950-2] [PMID: 10536220]
[38]
Tsuboi K, Kimber TA, Shults CW. Calretinin-containing axons and neurons are resistant to an intrastriatal 6-hydroxydopamine lesion. Brain Res 2000; 866(1-2): 55-64.
[http://dx.doi.org/10.1016/S0006-8993(00)02219-8] [PMID: 10825480]
[39]
Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 2008; 132(4): 598-611.
[http://dx.doi.org/10.1016/j.cell.2008.01.038] [PMID: 18295578]
[40]
Zhang RL, Zhang L, Zhang ZG, et al. Migration and differentiation of adult rat subventricular zone progenitor cells transplanted into the adult rat striatum. Neuroscience 2003; 116(2): 373-82.
[http://dx.doi.org/10.1016/S0306-4522(02)00696-6] [PMID: 12559093]
[41]
Blum D, Torch S, Lambeng N, et al. Molecular pathways involved in the neurotoxicity of 6-OHDA, dopamine and MPTP: contribution to the apoptotic theory in Parkinson’s disease. Prog Neurobiol 2001; 65(2): 135-72.
[http://dx.doi.org/10.1016/S0301-0082(01)00003-X] [PMID: 11403877]
[42]
Saito Y, Nishio K, Ogawa Y, et al. Molecular mechanisms of 6-hydroxydopamine-induced cytotoxicity in PC12 cells: involvement of hydrogen peroxide-dependent and -independent action. Free Radic Biol Med 2007; 42(5): 675-85.
[http://dx.doi.org/10.1016/j.freeradbiomed.2006.12.004] [PMID: 17291991]
[43]
Almond S, Lindley RM, Kenny SE, Connell MG, Edgar DH. Characterisation and transplantation of enteric nervous system progenitor cells. Gut 2007; 56(4): 489-96.
[http://dx.doi.org/10.1136/gut.2006.094565] [PMID: 16973717]
[44]
Fatima A, Jyoti S, Siddique YH. Models of Parkinson’s disease with special emphasis on Drosophila melanogaster. CNS Neurol Disord Drug Targets 2018; 17(10): 757-66.
[http://dx.doi.org/10.2174/1871527317666180820164250] [PMID: 30129420]
[45]
Jiang X, Tang P-C , Chen Q, et al. Cordycepin exerts neuroprotective effects via an anti-apoptotic mechanism based on the mitochondrial pathway in a rotenone-induced parkinsonism rat model. CNS Neurol Disord Drug Targets 2019; 18(8): 609-20.
[http://dx.doi.org/10.2174/1871527318666190905152138] [PMID: 31486758]
[46]
Ebada MA, Alkanj S, Ebada M, et al. Safety and efficacy of levetiracetam for the management of levodopa-induced dyskinesia in patients with Parkinson’s disease: a systematic review. CNS Neurol Disord Drug Targets 2019; 18(4): 317-25.
[http://dx.doi.org/10.2174/1871527318666190314101314] [PMID: 30868968]
[47]
Askar MH, Hussein AM, Al-Basiony SF, et al. Effects of exercise and ferulic acid on alpha synuclein and neuroprotective heat shock protein 70 in an experimental model of parkinsonism disease. CNS Neurol Disord Drug Targets 2019; 18(2): 156-69.
[http://dx.doi.org/10.2174/1871527317666180816095707] [PMID: 30113007]
[48]
Xu J, Cheng S, Jiao Z, et al. Fire needle acupuncture regulates Wnt/ERK multiple pathways to promote neural stem cells to differentiate into neurons in rats with spinal cord injury. CNS Neurol Disord Drug Targets 2019; 18(3): 245-55.
[http://dx.doi.org/10.2174/1871527318666190204111701] [PMID: 30714534]
[49]
Ibarra A, Mendieta-Arbesú E, Suarez-Meade P, et al. Motor recovery after chronic spinal cord transection in rats: a proof-of-concept study evaluating a combined strategy. CNS Neurol Disord Drug Targets 2019; 18(1): 52-62.
[http://dx.doi.org/10.2174/1871527317666181105101756] [PMID: 30394222]
[50]
Lasut B, Palasz A, Filipczyk L, et al. Long-term treatment with olanzapine increases the number of Sox2 and doublecortin expressing cells in the adult subventricular zone. CNS Neurol Disord Drug Targets 2018; 17(6): 458-63.
[http://dx.doi.org/10.2174/1871527317666180627113544] [PMID: 29952270]
[51]
Yang H, Yang Y, Qu S, et al. Growth Factor changes in cerebrospinal fluid of children with mental retardation before and after neural precursor cell transplantation. CNS Neurol Disord Drug Targets 2018; 17(2): 98-105.
[http://dx.doi.org/10.2174/1871527317666180411102337] [PMID: 29637872]
[52]
Qu S, Liu W, Yang H, et al. Clinical observation of electroencephalographic changes and risk of convulsion occurrence in children receiving neural precursor cell transplantation. CNS Neurol Disord Drug Targets 2018; 17(3): 233-9.
[http://dx.doi.org/10.2174/1871527317666180424121947] [PMID: 29692269]

Rights & Permissions Print Cite
Article Metrics
14
© 2024 Bentham Science Publishers | Privacy Policy