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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 spontaneous recurrent motor seizures (SRMSs) in pilocarpine-treated rats.The mean seizure frequencies (A), seizure stages (B) and total time spent in seizures (C) were calculated during 1, 2, and 3 months following transplantation in vehicle-injected and NSPC-transplanted groups. * Significantly different from the vehicle-injected group at P<0.05; error bars indicate ±SEM.
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pone-0104092-g008: Effect of human NSPC grafting on spontaneous recurrent motor seizures (SRMSs) in pilocarpine-treated rats.The mean seizure frequencies (A), seizure stages (B) and total time spent in seizures (C) were calculated during 1, 2, and 3 months following transplantation in vehicle-injected and NSPC-transplanted groups. * Significantly different from the vehicle-injected group at P<0.05; error bars indicate ±SEM.

Mentions: To examine the effect of huNSPCs transplantation on spontaneous seizures, we performed video monitoring in the pilocarpine model. Rats were video-monitored to document the emergence of SRMSs for 14–20 d after pilocarpine-induced SE. Previously, adult rats that underwent pilocarpine-induced SE for 1 h were reported to exhibit spontaneous seizures before 20 days after SE [24]. We also observed the emergence of at least one spontaneous seizure in all experimental animals. After confirmation of the occurrence of SRMSs, we injected NSPCs into both right and left hippocampus at 3 weeks after SE, and the rats were then video-monitored from 2 weeks to 3 months following transplantation. During the video monitoring period, we measured the frequency and severity of SRMS, and the total time spent in SRMS (Fig. 8). The mean frequencies of SRMSs in transplanted group (0.10±0.03 and 0.12±0.06 seizures/day at 2 and 3 months after grafting, respectively; n = 21) were significantly reduced compared with those in the vehicle group (0.26±0.06 and 0.61±0.15, respectively; n = 18; Fig. 8A). Thus, epileptic rats that received NSPC grafts into the hippocampus had significantly lower seizure frequencies as compared to vehicle-injected epileptic rats at 2 months (62% reduction, P = 0.029) and 3 months (80% reduction, P = 0.004) following transplantation. Seizure severity was usually stage 4 or 5. The mean seizure stage of SRMS was not different between both transplanted and vehicle groups (P>0.05; Fig. 8B). There were significant decreases in the average total time spent in SRMS at 2 and 3 months after grafting in the transplanted group (28.0±8.0 and 47.6±24.0 s, respectively) as compared to the corresponding time points in the vehicle group (69.0±16.9 and 213.5±51.5 s, respectively) (P = 0.033 and P = 0.007, respectively; Fig. 8C). The mean duration of individual SRMSs was not different in the transplanted group than in the vehicle group at any time point (P>0.05). The data suggest that huNSPCs grafting resulted in long-term significant attenuation of SRMS in a representative TLE model.


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 spontaneous recurrent motor seizures (SRMSs) in pilocarpine-treated rats.The mean seizure frequencies (A), seizure stages (B) and total time spent in seizures (C) were calculated during 1, 2, and 3 months following transplantation in vehicle-injected and NSPC-transplanted groups. * Significantly different from the vehicle-injected group at P<0.05; error bars indicate ±SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104092-g008: Effect of human NSPC grafting on spontaneous recurrent motor seizures (SRMSs) in pilocarpine-treated rats.The mean seizure frequencies (A), seizure stages (B) and total time spent in seizures (C) were calculated during 1, 2, and 3 months following transplantation in vehicle-injected and NSPC-transplanted groups. * Significantly different from the vehicle-injected group at P<0.05; error bars indicate ±SEM.
Mentions: To examine the effect of huNSPCs transplantation on spontaneous seizures, we performed video monitoring in the pilocarpine model. Rats were video-monitored to document the emergence of SRMSs for 14–20 d after pilocarpine-induced SE. Previously, adult rats that underwent pilocarpine-induced SE for 1 h were reported to exhibit spontaneous seizures before 20 days after SE [24]. We also observed the emergence of at least one spontaneous seizure in all experimental animals. After confirmation of the occurrence of SRMSs, we injected NSPCs into both right and left hippocampus at 3 weeks after SE, and the rats were then video-monitored from 2 weeks to 3 months following transplantation. During the video monitoring period, we measured the frequency and severity of SRMS, and the total time spent in SRMS (Fig. 8). The mean frequencies of SRMSs in transplanted group (0.10±0.03 and 0.12±0.06 seizures/day at 2 and 3 months after grafting, respectively; n = 21) were significantly reduced compared with those in the vehicle group (0.26±0.06 and 0.61±0.15, respectively; n = 18; Fig. 8A). Thus, epileptic rats that received NSPC grafts into the hippocampus had significantly lower seizure frequencies as compared to vehicle-injected epileptic rats at 2 months (62% reduction, P = 0.029) and 3 months (80% reduction, P = 0.004) following transplantation. Seizure severity was usually stage 4 or 5. The mean seizure stage of SRMS was not different between both transplanted and vehicle groups (P>0.05; Fig. 8B). There were significant decreases in the average total time spent in SRMS at 2 and 3 months after grafting in the transplanted group (28.0±8.0 and 47.6±24.0 s, respectively) as compared to the corresponding time points in the vehicle group (69.0±16.9 and 213.5±51.5 s, respectively) (P = 0.033 and P = 0.007, respectively; Fig. 8C). The mean duration of individual SRMSs was not different in the transplanted group than in the vehicle group at any time point (P>0.05). The data suggest that huNSPCs grafting resulted in long-term significant attenuation of SRMS in a representative TLE model.

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