Limits...
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.

Show MeSH

Related in: MedlinePlus

Effect of human NSPC grafting on spatial learning and memory function in the pilocarpine-treated rats.(A) Latency to locate the hidden platform (escape latency) was recorded. In the age-matched intact controls, escape latency decreased gradually and significantly over the 4 days of testing, indicating excellent spatial learning. In contrast, NSPC- and vehicle-injected epileptic rats showed markedly longer latency to escape the maze than intact controls (P = 0.024 and P = 0.006, respectively). (B–E) During probe testing on day 5, parameters of memory retention were measured in the three groups: dwell time in the target quadrant (B), dwell time in the platform area (C), latency to the platform (D), and platform area crossings (E). Vehicle-injected epileptic rats exhibited significant deficits in memory retention in terms of all parameters. NSPC-transplanted epileptic rats also showed significant memory deficits, except dwell time in the platform area. * Significantly different from age-matched intact controls at P<0.05; error bars indicate ±SEM.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4126719&req=5

pone-0104092-g009: Effect of human NSPC grafting on spatial learning and memory function in the pilocarpine-treated rats.(A) Latency to locate the hidden platform (escape latency) was recorded. In the age-matched intact controls, escape latency decreased gradually and significantly over the 4 days of testing, indicating excellent spatial learning. In contrast, NSPC- and vehicle-injected epileptic rats showed markedly longer latency to escape the maze than intact controls (P = 0.024 and P = 0.006, respectively). (B–E) During probe testing on day 5, parameters of memory retention were measured in the three groups: dwell time in the target quadrant (B), dwell time in the platform area (C), latency to the platform (D), and platform area crossings (E). Vehicle-injected epileptic rats exhibited significant deficits in memory retention in terms of all parameters. NSPC-transplanted epileptic rats also showed significant memory deficits, except dwell time in the platform area. * Significantly different from age-matched intact controls at P<0.05; error bars indicate ±SEM.

Mentions: Epilepsy in patients is often accompanied by cognitive decline [46]. Thus, we examined whether huNSPC transplantation could affect performance in a Morris water maze test, which assesses hippocampal-dependent learning and memory function. To estimate the effect of NSPC transplantation on learning and memory function in the pilocarpine model, we performed water maze testing at 3 months post-grafting. Age-matched intact controls (n = 6) showed the marked decreases in the escape latencies over the sessions, indicating normal spatial learning ability. However, epileptic rats in the vehicle group (n = 11) did not improve significantly in locating the submerged platform over the trials (Fig. 9A), consistent with other reports, demonstrating impaired spatial learning [47], [48]. During the probe test to evaluate the memory function, epileptic rats in the vehicle group spent significantly shorter times in the target quadrant and in the platform area (Fig. 9B, C), took longer to reach the platform area (Fig. 9D), and barely crossed the platform area compared with intact controls (Fig. 9E). In the transplantation group (n = 12), rats did not show amelioration in overall spatial learning or memory function, and were not considerably different from the vehicle-injected group.


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 spatial learning and memory function in the pilocarpine-treated rats.(A) Latency to locate the hidden platform (escape latency) was recorded. In the age-matched intact controls, escape latency decreased gradually and significantly over the 4 days of testing, indicating excellent spatial learning. In contrast, NSPC- and vehicle-injected epileptic rats showed markedly longer latency to escape the maze than intact controls (P = 0.024 and P = 0.006, respectively). (B–E) During probe testing on day 5, parameters of memory retention were measured in the three groups: dwell time in the target quadrant (B), dwell time in the platform area (C), latency to the platform (D), and platform area crossings (E). Vehicle-injected epileptic rats exhibited significant deficits in memory retention in terms of all parameters. NSPC-transplanted epileptic rats also showed significant memory deficits, except dwell time in the platform area. * Significantly different from age-matched intact controls 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-g009: Effect of human NSPC grafting on spatial learning and memory function in the pilocarpine-treated rats.(A) Latency to locate the hidden platform (escape latency) was recorded. In the age-matched intact controls, escape latency decreased gradually and significantly over the 4 days of testing, indicating excellent spatial learning. In contrast, NSPC- and vehicle-injected epileptic rats showed markedly longer latency to escape the maze than intact controls (P = 0.024 and P = 0.006, respectively). (B–E) During probe testing on day 5, parameters of memory retention were measured in the three groups: dwell time in the target quadrant (B), dwell time in the platform area (C), latency to the platform (D), and platform area crossings (E). Vehicle-injected epileptic rats exhibited significant deficits in memory retention in terms of all parameters. NSPC-transplanted epileptic rats also showed significant memory deficits, except dwell time in the platform area. * Significantly different from age-matched intact controls at P<0.05; error bars indicate ±SEM.
Mentions: Epilepsy in patients is often accompanied by cognitive decline [46]. Thus, we examined whether huNSPC transplantation could affect performance in a Morris water maze test, which assesses hippocampal-dependent learning and memory function. To estimate the effect of NSPC transplantation on learning and memory function in the pilocarpine model, we performed water maze testing at 3 months post-grafting. Age-matched intact controls (n = 6) showed the marked decreases in the escape latencies over the sessions, indicating normal spatial learning ability. However, epileptic rats in the vehicle group (n = 11) did not improve significantly in locating the submerged platform over the trials (Fig. 9A), consistent with other reports, demonstrating impaired spatial learning [47], [48]. During the probe test to evaluate the memory function, epileptic rats in the vehicle group spent significantly shorter times in the target quadrant and in the platform area (Fig. 9B, C), took longer to reach the platform area (Fig. 9D), and barely crossed the platform area compared with intact controls (Fig. 9E). In the transplantation group (n = 12), rats did not show amelioration in overall spatial learning or memory function, and were not considerably different from the vehicle-injected group.

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