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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.

Lee H, Yun S, Kim IS, Lee IS, Shin JE, Park SC, Kim WJ, Park KI - PLoS ONE (2014)

Bottom Line: However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals.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.

View Article: PubMed Central - PubMed

Affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.

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.

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Effect of human NSPC grafting on hippocampal-kindled seizures in rats.The mean values of afterdischarge duration (ADD) in electroencephalograms (A), behavioral seizure duration (B), and seizure stage (C) between vehicle-injected and NSPC-transplanted groups were compared before (pre-Tx) and after NSPC grafting (post-Tx). Error bars indicate ±SEM. huNSPC grafting significantly reduced all three seizure parameters—ADD, behavioral seizure duration, and seizure stage—although this seizure-suppressing effect was not permanent. * Significantly different from the vehicle-injected group at P<0.05; ** significantly different from the vehicle-injected group at P<0.01.
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pone-0104092-g007: Effect of human NSPC grafting on hippocampal-kindled seizures in rats.The mean values of afterdischarge duration (ADD) in electroencephalograms (A), behavioral seizure duration (B), and seizure stage (C) between vehicle-injected and NSPC-transplanted groups were compared before (pre-Tx) and after NSPC grafting (post-Tx). Error bars indicate ±SEM. huNSPC grafting significantly reduced all three seizure parameters—ADD, behavioral seizure duration, and seizure stage—although this seizure-suppressing effect was not permanent. * Significantly different from the vehicle-injected group at P<0.05; ** significantly different from the vehicle-injected group at P<0.01.

Mentions: The effect of huNSPCs transplantation on kindled seizure activity was evaluated weekly for 8 weeks following transplantation. Compared with the vehicle-injected group (n = 13), the transplanted group (n = 12) showed substantial decreases in three seizure parameters—ADD on EEG examination, behavioral seizure duration, and seizure stage—although no significant difference was observed in seizure parameters between pre-grafts in both groups (Fig. 7A–C). In the transplanted group, ADD decreased steadily until 4 weeks after grafting and significantly decreased compared with the vehicle group at the third week (24% reduction, P = 0.047) and fourth week (39% reductions, P = 0.005) (Fig. 7A).


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

Lee H, Yun S, Kim IS, Lee IS, Shin JE, Park SC, Kim WJ, Park KI - PLoS ONE (2014)

Effect of human NSPC grafting on hippocampal-kindled seizures in rats.The mean values of afterdischarge duration (ADD) in electroencephalograms (A), behavioral seizure duration (B), and seizure stage (C) between vehicle-injected and NSPC-transplanted groups were compared before (pre-Tx) and after NSPC grafting (post-Tx). Error bars indicate ±SEM. huNSPC grafting significantly reduced all three seizure parameters—ADD, behavioral seizure duration, and seizure stage—although this seizure-suppressing effect was not permanent. * Significantly different from the vehicle-injected group at P<0.05; ** significantly different from the vehicle-injected group at P<0.01.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4126719&req=5

pone-0104092-g007: Effect of human NSPC grafting on hippocampal-kindled seizures in rats.The mean values of afterdischarge duration (ADD) in electroencephalograms (A), behavioral seizure duration (B), and seizure stage (C) between vehicle-injected and NSPC-transplanted groups were compared before (pre-Tx) and after NSPC grafting (post-Tx). Error bars indicate ±SEM. huNSPC grafting significantly reduced all three seizure parameters—ADD, behavioral seizure duration, and seizure stage—although this seizure-suppressing effect was not permanent. * Significantly different from the vehicle-injected group at P<0.05; ** significantly different from the vehicle-injected group at P<0.01.
Mentions: The effect of huNSPCs transplantation on kindled seizure activity was evaluated weekly for 8 weeks following transplantation. Compared with the vehicle-injected group (n = 13), the transplanted group (n = 12) showed substantial decreases in three seizure parameters—ADD on EEG examination, behavioral seizure duration, and seizure stage—although no significant difference was observed in seizure parameters between pre-grafts in both groups (Fig. 7A–C). In the transplanted group, ADD decreased steadily until 4 weeks after grafting and significantly decreased compared with the vehicle group at the third week (24% reduction, P = 0.047) and fourth week (39% reductions, P = 0.005) (Fig. 7A).

Bottom Line: However, NSPC grafting neither improved spatial learning or memory function in pilocarpine-treated animals.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.

View Article: PubMed Central - PubMed

Affiliation: Brain Korea 21 Plus Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.

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.

Show MeSH
Related in: MedlinePlus