Transplantation of neurogenic-fusionogenic embryonic stem cells modified to overexpress GABA into a model of temporal lobe epilepsy: Promises and potential pitfalls.
Main Article Content
Abstract
Cell-based therapy is likely to become a clinically useful tool to treat severe neurological disease. Disease states such as intractable temporal lobe epilepsy will be candidates for this type of therapeutic approach. Embryonic stem cells are pluripotent, and are considered a viable source for cell replacement strategies. Embryonic stem cells can be genetically manipulated to express reporter molecules, and they can be forced into neural differentiation by controlling the expression of key transcription factors. One strategy for the treatment of temporal lobe epilepsy is to transplant enriched populations of transplantable GABAergic neurons into the damaged, epileptogenic, hippocampus. The goal would be to suppress seizures, and to replace and repair damaged circuits. We genetically engineered an embryonic stem cell -derived neurogenic, fusionogenic cell line with GAD65 and transplanted them into an animal model of temporal lobe epilepsy. We found some evidence of seizure suppression, and also evidence of widespread dispersion from the transplantation site. The pattern of staining of embryonic stem cell reporter molecule that was detected, suggested a pathotropism, and selective involvement of reportedly fusionogenic cell populations within the host. We feel that the evidence suggests that embryonic stem cell-derived neural cells might have a significant capacity to fuse with host neurons, which can cloud the interpretation of cellular replacement and circuit repair. This study, and other investigations that have reported stem cell fusion events in the transplanted host, reveal embryonic stem cell capacities that may not be fully appreciated. More research is needed to fully reveal the potential of cellular therapies using stem cells.
Keywords:
Transplantation of neurogenic-fusionogenic embryonic stem cells, temporal lobe epilepsy
Article Details
How to Cite
THOMPSON, Kerry et al.
Transplantation of neurogenic-fusionogenic embryonic stem cells modified to overexpress GABA into a model of temporal lobe epilepsy: Promises and potential pitfalls..
Medical Research Archives, [S.l.], v. 11, n. 10, oct. 2023.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/4510>. Date accessed: 15 may 2024.
doi: https://doi.org/10.18103/mra.v11i10.4510.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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2. Golub VM, Reddy DS. Post-Traumatic Epilepsy and Comorbidities: Advanced Models, Molecular Mechanisms, Biomarkers, and Novel Therapeutic Interventions. Pharmacol Rev. Apr 2022;74(2):387-438. doi: 10.1124/pharmrev.121.000375
3. Holtkamp M, Beghi E, Benninger F, et al. European Stroke Organisation guidelines for the management of post-stroke seizures and epilepsy. Eur Stroke J. Jun 2017;2(2):103-115. doi:10.1177/2396987317705536
4. Mazarati A, Bragin A, Baldwin R, et al. Epileptogenesis after self-sustaining status epilepticus. Epilepsia. 2002;43 Suppl 5:74-80.
5. Shibley H, Smith BN. Pilocarpine-induced status epilepticus results in mossy fiber sprouting and spontaneous seizures in C57BL/6 and CD-1 mice. Epilepsy Research. 2002;49(2):109-20.
6. Shirasaka Y, Wasterlain CG. Chronic epileptogenicity following focal status epilepticus. Brain Research. 1994;655(1-2):33-44.
7. Sloviter RS. Permanently altered hippocampal structure, excitability, and inhibition after experimental status epilepticus in the rat: the "dormant basket cell" hypothesis and its possible relevance to temporal lobe epilepsy. Hippocampus. 1991;1(1):41-66.
8. Thompson K, Wasterlain C. Lithium-pilocarpine status epilepticus in the immature rabbit. Brain Res Dev Brain Res. 1997;100 (1):1-4.
9. Thompson KW, Suchomelova L, Wasterlain CG. Treatment of early life status epilepticus: What can we learn from animal models? Epilepsia Open. Dec 2018;3(Suppl Suppl 2):169-179. doi:10.1002/epi4.12271
10. H.J. T, McCormick WC, Kagan SH. Traumatic brain injury in older adults: epidemiology, outcomes, and future implications. Journal of American Geriatric Society. 2006;54(10):1590-1595.
11. Kwan P, Brodie MJ. Definition of refractory epilepsy: defining the indefinable? Lancet Neurol. Jan 2010;9(1):27-9. doi:10.1016/S1474-4422(09)70304-7
12. Rausch R. Epilepsy surgery within the temporal lobe and its short-term and long-term effects on memory. Current Opinion in Neurology. 2002;15(2):185-9.
13. Salanova V, Markand O, Worth R. Temporal lobe epilepsy surgery: outcome, complications, and late mortality rate in 215 patients. Epilepsia. 2002;43(2):170-4.
14. Loscher W, Gernert M, Heinemann U. Cell and gene therapies in epilepsy--promising avenues or blind alleys? Trends Neurosci. Feb 2008;31(2):62-73.
15. Frisina F, Valetti G, Zuccarini G, Conti L, Merlo GR. Advances in the use of GABAergic interneurons for the treatment of epilepsy. Journal of Stem Cell Therapy and Transplantation. 2019;3:9-22. doi:10.29328/ journal.jsctt.1001014
16. Thompson K. Transplantation of GABA-producing cells for seizure control in models of temporal lobe epilepsy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. Apr 2009;6 (2):284-94. doi:10.1016/j.nurt.2009.01.016
17. Bonaventura G, Munafo A, Bellanca CM, et al. Stem Cells: Innovative Therapeutic Options for Neurodegenerative Diseases? Cells. Aug 5 2021;10(8)doi:10.3390/ cells 10081992
18. Gernert M, Thompson KW, Loscher W, Tobin AJ. Genetically engineered GABA-producing cells demonstrate anticonvulsant effects and long-term transgene expression when transplanted into the central piriform cortex of rats. Exp Neurol. Jul 2002;176 (1):183-92.
19. Thompson KW. Genetically engineered cells with regulatable GABA production can affect afterdischarges and behavioral seizures after transplantation into the dentate gyrus. Neuroscience. 2005;133(4):1029-37.
20. Thompson KW, Suchomelova LM. Transplants of cells engineered to produce GABA suppress spontaneous seizures. Epilepsia. 2004;45(1):4-12.
21. Behrstock SP, Anantharam V, Thompson KW, Schweitzer ES, Tobin AJ. Conditionally-immortalized astrocytic cell line expresses GAD and secretes GABA under tetracycline regulation. J Neurosci Res. 2000;60(3):302-10.
22. Henriques D, Moreira R, Schwamborn J, Pereira de Almeida L, Mendonca LS. Successes and Hurdles in Stem Cells Application and Production for Brain Transplantation. Front Neurosci. 2019;13: 1194. doi:10.3389/fnins.2019.01194
23. Shetty AK, Upadhya D. GABA-ergic cell therapy for epilepsy: Advances, limitations and challenges. Neurosci Biobehav Rev. Mar 2016;62:35-47. doi:10.1016/j.neubiorev.2015 .12.014
24. Au E, Ahmed T, Karayannis T, Biswas S, Gan L, Fishell G. A modular gain-of-function approach to generate cortical interneuron subtypes from ES cells. Neuron. Dec 4 2013;80(5):1145-58. doi:10.1016/j.neuron.2013.09.022
25. Tyson JA, Goldberg EM, Maroof AM, Xu Q, Petros TJ, Anderson SA. Duration of culture and sonic hedgehog signaling differentially specify PV versus SST cortical interneuron fates from embryonic stem cells. Development. Apr 1 2015;142(7):1267-78. doi:10.1242/dev.111526
26. Chu K, Kim M, Jung KH, et al. Human neural stem cell transplantation reduces spontaneous recurrent seizures following pilocarpine-induced status epilepticus in adult rats. Brain Res. Oct 15 2004;1023(2):213-21.
27. Carpentino JE, Hartman NW, Grabel LB, Naegele JR. Region-specific differentiation of embryonic stem cell-derived neural progenitor transplants into the adult mouse hippocampus following seizures. J Neurosci Res. Feb 15 2008;86(3):512-24.
28. Maisano X, Litvina E, Tagliatela S, Aaron GB, Grabel LB, Naegele JR. Differentiation and functional incorporation of embryonic stem cell-derived GABAergic interneurons in the dentate gyrus of mice with temporal lobe epilepsy. J Neurosci. Jan 4 2012;32(1):46-61. doi:10.1523/JNEUROSCI.2683-11.2012
29. Alvarez-Dolado M, Pardal R, Garcia-Verdugo JM, et al. Fusion of bone-marrow-derived cells with Purkinje neurons, cardiomyocytes and hepatocytes. Nature. Oct 30 2003;425 (6961) :968-73. doi:10.1038 /nature02069
30. Jessberger S, Clemenson GD, Jr., Gage FH. Spontaneous fusion and nonclonal growth of adult neural stem cells. Stem Cells. Apr 2007;25(4):871-4. doi:10.1634/stemcells.2006-0620
31. Johansson CB, Youssef S, Koleckar K, et al. Extensive fusion of haematopoietic cells with Purkinje neurons in response to chronic inflammation. Nature cell biology. May 2008;10(5):575-83. doi:10.1038/ncb1720
32. Kemp K, Gray E, Wilkins A, Scolding N. Purkinje cell fusion and binucleate heterokaryon formation in multiple sclerosis cerebellum. Brain : a journal of neurology. Oct 2012;135(Pt 10) :2962-72. doi:10.1093/brain/ aws226
33. Kozorovitskiy Y, Gould E. Stem cell fusion in the brain. Nature cell biology. Nov 2003;5(11):952-4. doi:10.1038/ncb1103-952
34. Nern C, Wolff I, Macas J, et al. Fusion of hematopoietic cells with Purkinje neurons does not lead to stable heterokaryon formation under noninvasive conditions. J Neurosci. Mar 25 2009;29(12):3799-807. doi:10.1523/jneurosci.5848-08.2009
35. Kimes EK, M; Amri, D, Noone A; Barron J; Saito, A; Cortez-Toledo, O; Cortez-Toledo, E; Arrizon, D; Quist, J; Balderas, Y; Miranda, M; Tran, T; Kim, F; Thompson, K. Neurogenic Stem Cells Have the Capacity to Disperse Widely and Fuse with Host Neurons in Adult Rats. Journal of Stem Cell Research and Transplantation. 2014;1(2)
36. Brilli E, Reitano E, Conti L, et al. Neural stem cells engrafted in the adult brain fuse with endogenous neurons. Stem Cells Dev. Feb 15 2013;22(4):538-47. doi:10.1089/ scd.2012.0530
37. Cusulin C, Monni E, Ahlenius H, et al. Embryonic stem cell-derived neural stem cells fuse with microglia and mature neurons. Stem Cells. Dec 2012;30(12):2657-71. doi:10.1002/ stem.1227
38. Chen KA, Cruz PE, Lanuto DJ, et al. Cellular fusion for gene delivery to SCA1 affected Purkinje neurons. Molecular and cellular neurosciences. May 2011;47(1):61-70. doi:10.1016/j.mcn.2011.03.003
39. Espejel S, Romero R, Alvarez-Buylla A. Radiation damage increases Purkinje neuron heterokaryons in neonatal cerebellum. Annals of neurology. Jul 2009;66 (1):100-9. doi: 10.1002/ana.21670
40. Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells. Nat Genet. Apr 2000;24(4):372-6.
41. Niwa H, Miyazaki J, Smith AG. Quantitative expression of Oct-3/4 defines differentiation, dedifferentiation or self-renewal of ES cells.[see comment]. Nature Genetics. 2000;24(4):372-6.
42. Thompson K, Anantharam V, Behrstock S, Bongarzone E, Campagnoni A, Tobin AJ. Conditionally immortalized cell lines, engineered to produce and release GABA, modulate the development of behavioral seizures. Experimental Neurology. 2000;161 (2):481-9.
43. Wasterlain CG, Niquet J, Thompson KW, et al. Seizure-induced neuronal death in the immature brain. Progress in Brain Research. 2002;135:335-53.
44. Cenci MA, Lee CS, Bjorklund A. L-DOPA-induced dyskinesia in the rat is associated with striatal overexpression of prodynorphin- and glutamic acid decarboxylase mRNA. European Journal of Neuroscience. 1998;10 (8):2694-706.
45. Lundblad M, Andersson M, Winkler C, Kirik D, Wierup N, Cenci MA. Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease. Eur J Neurosci. Jan 2002;15(1):120-32.
46. Lane EL, Winkler C, Brundin P, Cenci MA. The impact of graft size on the development of dyskinesia following intrastriatal grafting of embryonic dopamine neurons in the rat. Neurobiol Dis. 2006;22(2):334-45. Epub 2006 Jan 10.
47. Shimozaki K, Nakashima K, Niwa H, Taga T. Involvement of Oct3/4 in the enhancement of neuronal differentiation of ES cells in neurogenesis-inducing cultures. Development Jun 2003;130(11):2505-12.
48. Fraichard A, Chassande O, Bilbaut G, Dehay C, Savatier P, Samarut J. In vitro differentiation of embryonic stem cells into glial cells and functional neurons. Journal of Cell Science. 1995;108(Pt 10):3181-8.
49. Schwarzer C, Williamson JM, Lothman EW, Vezzani A, Sperk G. Somatostatin, neuropeptide Y, neurokinin B and cholecystokinin immunoreactivity in two chronic models of temporal lobe epilepsy. Neuroscience. Dec 1995;69(3):831-45. doi: 10.1016/0306-4522(95)00268-n
50. Ideguchi M, Palmer TD, Recht LD, Weimann JM. Murine embryonic stem cell-derived pyramidal neurons integrate into the cerebral cortex and appropriately project axons to subcortical targets. J Neurosci. Jan 20 2010;30 (3) :894-904. doi:10.1523/ JNEUROSCI.4318-09.2010
51. Shetty AK, Hattiangady B. Concise review: prospects of stem cell therapy for temporal lobe epilepsy. Stem Cells. Oct 2007;25(10):2396-407.
52. Appaix F, Nissou MF, van der Sanden B, et al. Brain mesenchymal stem cells: The other stem cells of the brain? World journal of stem cells. Apr 26 2014;6(2):134-43. doi:10.4252 /wjsc.v6.i2.134
53. Kemp K, Gordon D, Wraith DC, et al. Fusion between human mesenchymal stem cells and rodent cerebellar Purkinje cells. Neuropathology and applied neurobiology. Feb 2011;37(2):166-78. doi:10.1111/j.1365-2990.2010.01122.x
54. Thompson K. Genetically engineered neural cells with controllable GABA or DOPA production: a possible method to control side effects after transplantation. 2nd VA/UCLA Research Conference on Parkinson's Disease and Movement Disorders. 2004;29
55. Ruschenschmidt C, Koch PG, Brustle O, Beck H. Functional properties of ES cell-derived neurons engrafted into the hippocampus of adult normal and chronically epileptic rats. Epilepsia. 2005;46 Suppl 5:174-83.
56. Weimann JM, Johansson CB, Trejo A, Blau HM. Stable reprogrammed heterokaryons form spontaneously in Purkinje neurons after bone marrow transplant. Nature cell biology. Nov 2003;5(11):959-66. doi: 10.1038/ncb1053
57. Zhou X, Platt JL. Molecular and cellular mechanisms of mammalian cell fusion. Adv Exp Med Biol. 2011;713:33-64. doi:10.1007 /978-94-007-0763-4_4
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