title: Human fetal brain-derived neural stem/progenitor cells grafted into the adult epileptic brain restrain seizures in rat models of temporal lobe epilepsy.
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.
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Haejin
authors.initials: H
authors.lastname: Lee
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Seokhwan
authors.initials: S
authors.lastname: Yun
authors.affiliation: Severance Children's Hospital, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Il-Sun
authors.initials: IS
authors.lastname: Kim
authors.affiliation: Severance Children's Hospital, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Il-Shin
authors.initials: IS
authors.lastname: Lee
authors.affiliation: Severance Children's Hospital, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Shin
authors.affiliation: Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Soo Chul
authors.initials: SC
authors.lastname: Park
authors.affiliation: Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Won-Joo
authors.initials: WJ
authors.lastname: Kim
authors.affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea; Severance Children's Hospital, Department of Pediatrics, Yonsei University College of Medicine, Seoul, Korea.
authors.forename: Kook In
authors.initials: KI
authors.lastname: Park
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D015153:Blotting, Western; D001921:Brain / Q000166:cytology / Q000378:metabolism*; D002454:Cell Differentiation / Q000502:physiology*; D002851:Chromatography, High Pressure Liquid; D004569:Electroencephalography; D004833:Epilepsy, Temporal Lobe / Q000628:therapy*; D005333:Fetus / Q000166:cytology*; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D006801:Humans; D019599:Mossy Fibers, Hippocampal / Q000378:metabolism; D058953:Neural Stem Cells / Q000637:transplantation*; D010862:Pilocarpine; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D016896:Treatment Outcome; D005680:gamma-Aminobutyric Acid / Q000378:metabolism
chemical_list: D051100:Glial Cell Line-Derived Neurotrophic Factor; D010862:Pilocarpine; D005680:gamma-Aminobutyric Acid
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