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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 the expression of GDNF in host hippocampal astrocytes.GDNF expression in S100β+ hippocampal astrocyte was observed in an age-matched intact control (A–D), vehicle-injected pilocarpine-treated (E–H), and NSPC-transplanted pilocarpine-treated rats (I–L). Nuclei were counterstained with DAPI (C, G, and K). Arrowheads in A–L indicated S100β/GDNF double-labeled cells. Arrows in E, G and H denoted S100β+ host hippocampal astrocytes that were devoid of GDNF immunoreactivity in vehicle-injected epileptic rats. Scale bar, 50 µm. (M) The bar chart represents percentages of S100β+ astrocytes expressing GDNF in the CA3 region of the hippocampus in the three groups. There was a significant difference between intact controls and vehicle-injected epileptic rats (P = 0.022) and between vehicle-injected and NSPC-transplanted epileptic rats (P = 0.038). * Significantly different from the age-matched intact control group at P<0.05; † significantly different from vehicle-injected group at P<0.05; error bars indicate ±SEM.
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pone-0104092-g010: Effect of human NSPC grafting on the expression of GDNF in host hippocampal astrocytes.GDNF expression in S100β+ hippocampal astrocyte was observed in an age-matched intact control (A–D), vehicle-injected pilocarpine-treated (E–H), and NSPC-transplanted pilocarpine-treated rats (I–L). Nuclei were counterstained with DAPI (C, G, and K). Arrowheads in A–L indicated S100β/GDNF double-labeled cells. Arrows in E, G and H denoted S100β+ host hippocampal astrocytes that were devoid of GDNF immunoreactivity in vehicle-injected epileptic rats. Scale bar, 50 µm. (M) The bar chart represents percentages of S100β+ astrocytes expressing GDNF in the CA3 region of the hippocampus in the three groups. There was a significant difference between intact controls and vehicle-injected epileptic rats (P = 0.022) and between vehicle-injected and NSPC-transplanted epileptic rats (P = 0.038). * Significantly different from the age-matched intact control group at P<0.05; † significantly different from vehicle-injected group at P<0.05; error bars indicate ±SEM.

Mentions: Increased GDNF levels in hippocampal astrocytes of the epileptic brain are known to suppress seizures [49], [50]. In this study, few huNSPC-derived cells after grafting differentiated into GDNF-expressing astrocytes in the hippocampus in either TLE model. However, NSPC transplantation induced GDNF expression in a large part (>80%, n = 6) of host hippocampal astrocytes in the pilocarpine-treated TLE model, whereas the level of GDNF expression of host astrocytes was ∼72% (n = 4) in age-matched intact controls and ∼46% (n = 6) in vehicle-injected epileptic rats (Fig. 10). This suggested that the level of GDNF expression was restored to closer to that of the intact controls after NSPCs grafting. Thus, the induction of GDNF expression in host hippocampal astrocytes by huNSPCs transplantation may be involved in suppressing seizures.


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 the expression of GDNF in host hippocampal astrocytes.GDNF expression in S100β+ hippocampal astrocyte was observed in an age-matched intact control (A–D), vehicle-injected pilocarpine-treated (E–H), and NSPC-transplanted pilocarpine-treated rats (I–L). Nuclei were counterstained with DAPI (C, G, and K). Arrowheads in A–L indicated S100β/GDNF double-labeled cells. Arrows in E, G and H denoted S100β+ host hippocampal astrocytes that were devoid of GDNF immunoreactivity in vehicle-injected epileptic rats. Scale bar, 50 µm. (M) The bar chart represents percentages of S100β+ astrocytes expressing GDNF in the CA3 region of the hippocampus in the three groups. There was a significant difference between intact controls and vehicle-injected epileptic rats (P = 0.022) and between vehicle-injected and NSPC-transplanted epileptic rats (P = 0.038). * Significantly different from the age-matched intact control group at P<0.05; † significantly different from 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-g010: Effect of human NSPC grafting on the expression of GDNF in host hippocampal astrocytes.GDNF expression in S100β+ hippocampal astrocyte was observed in an age-matched intact control (A–D), vehicle-injected pilocarpine-treated (E–H), and NSPC-transplanted pilocarpine-treated rats (I–L). Nuclei were counterstained with DAPI (C, G, and K). Arrowheads in A–L indicated S100β/GDNF double-labeled cells. Arrows in E, G and H denoted S100β+ host hippocampal astrocytes that were devoid of GDNF immunoreactivity in vehicle-injected epileptic rats. Scale bar, 50 µm. (M) The bar chart represents percentages of S100β+ astrocytes expressing GDNF in the CA3 region of the hippocampus in the three groups. There was a significant difference between intact controls and vehicle-injected epileptic rats (P = 0.022) and between vehicle-injected and NSPC-transplanted epileptic rats (P = 0.038). * Significantly different from the age-matched intact control group at P<0.05; † significantly different from vehicle-injected group at P<0.05; error bars indicate ±SEM.
Mentions: Increased GDNF levels in hippocampal astrocytes of the epileptic brain are known to suppress seizures [49], [50]. In this study, few huNSPC-derived cells after grafting differentiated into GDNF-expressing astrocytes in the hippocampus in either TLE model. However, NSPC transplantation induced GDNF expression in a large part (>80%, n = 6) of host hippocampal astrocytes in the pilocarpine-treated TLE model, whereas the level of GDNF expression of host astrocytes was ∼72% (n = 4) in age-matched intact controls and ∼46% (n = 6) in vehicle-injected epileptic rats (Fig. 10). This suggested that the level of GDNF expression was restored to closer to that of the intact controls after NSPCs grafting. Thus, the induction of GDNF expression in host hippocampal astrocytes by huNSPCs transplantation may be involved in suppressing seizures.

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