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Human fetal brain-derived neural stem/progenitor cells grafted into the adult epileptic brain restrain seizures in rat models of temporal lobe epilepsy

Authors
 Haejin Lee  ;  Seokhwan Yun  ;  Il-Sun Kim  ;  Il-Shin Lee  ;  Jeong Eun Shin  ;  Soo Chul Park  ;  Won-Joo Kim  ;  Kook In Park 
Citation
 PLOS ONE, Vol.9(8) : e104092, 2014 
Journal Title
 PLOS ONE 
Issue Date
2014
MeSH
Analysis of Variance ; Animals ; Blotting, Western ; Brain/cytology ; Brain/metabolism* ; Cell Differentiation/physiology* ; Chromatography, High Pressure Liquid ; Electroencephalography ; Epilepsy, Temporal Lobe/therapy* ; Fetus/cytology* ; Glial Cell Line-Derived Neurotrophic Factor/metabolism ; Humans ; Mossy Fibers, Hippocampal/metabolism ; Neural Stem Cells/transplantation* ; Pilocarpine ; Rats ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Statistics, Nonparametric ; Treatment Outcome ; gamma-Aminobutyric Acid/metabolism
Abstract
Cell transplantation has been suggested as an alternative therapy for temporal lobe epilepsy (TLE) because this can suppress spontaneous recurrent seizures in animal models. To evaluate the therapeutic potential of human neural stem/progenitor cells (huNSPCs) for treating TLE, we transplanted huNSPCs, derived from an aborted fetal telencephalon at 13 weeks of gestation and expanded in culture as neurospheres over a long time period, into the epileptic hippocampus of fully kindled and pilocarpine-treated adult rats exhibiting TLE. In vitro, huNSPCs not only produced all three central nervous system neural cell types, but also differentiated into ganglionic eminences-derived γ-aminobutyric acid (GABA)-ergic interneurons and released GABA in response to the depolarization induced by a high K+ medium. NSPC grafting reduced behavioral seizure duration, afterdischarge duration on electroencephalograms, and seizure stage in the kindling model, as well as the frequency and the duration of spontaneous recurrent motor seizures in pilocarpine-induced animals. However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals. Following transplantation, grafted cells showed extensive migration around the injection site, robust engraftment, and long-term survival, along with differentiation into β-tubulin III+ neurons (~34%), APC-CC1+ oligodendrocytes (~28%), and GFAP+ astrocytes (~8%). Furthermore, among donor-derived cells, ~24% produced GABA. Additionally, to explain the effect of seizure suppression after NSPC grafting, we examined the anticonvulsant glial cell-derived neurotrophic factor (GDNF) levels in host hippocampal astrocytes and mossy fiber sprouting into the supragranular layer of the dentate gyrus in the epileptic brain. Grafted cells restored the expression of GDNF in host astrocytes but did not reverse the mossy fiber sprouting, eliminating the latter as potential mechanism. These results suggest that human fetal brain-derived NSPCs possess some therapeutic effect for TLE treatments although further studies to both increase the yield of NSPC grafts-derived functionally integrated GABAergic neurons and improve cognitive deficits are still needed.
Files in This Item:
T201402833.pdf Download
DOI
10.1371/journal.pone.0104092
Appears in Collections:
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pediatrics (소아청소년과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Neurology (신경과학교실) > 1. Journal Papers
Yonsei Authors
Kim, Won Joo(김원주) ORCID logo https://orcid.org/0000-0002-5850-010X
Kim, Il-Sun(김일선) ORCID logo https://orcid.org/0000-0003-4033-4323
Park, Kook In(박국인) ORCID logo https://orcid.org/0000-0001-8499-9293
Park, Soo Chul(박수철)
Yun, Seok Hwan(윤석환)
Lee, Il Shin(이일신)
Lee, Hae Jin(이혜진)
URI
https://ir.ymlib.yonsei.ac.kr/handle/22282913/99607
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