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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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Engraftment and distribution of human NSPCs into the hippocampus of kindled rats.(A–E) Serial sections (320 µm apart) throughout the hippocampus were used to determine the location of BrdU+ grafted cells, visualized with fluorescein at 4 weeks following transplantation. A–E panels are representative images of serial coronal sections of the hippocampus which are ordered from anterior to posterior. Grafted cells had migrated apart from the injection site (arrowhead in C) and dispersed throughout the adjacent hippocampal subfields. Many grafted cells were predominantly placed in the radiatum layer (Rad) of the CA3 region, molecular (ML) and granular cell layer (GCL) of the dentate gyrus (DG), and hilus (HI) of the hippocampus. Dotted lines denote the boundary between HI and GCL of the DG. In panel C, the boxed regions of the Rad (1), and ML, GCL and HI (2) are magnified in panel C-1 and C-2, respectively. Scale bar, 500 µm (A–E) and 100 µm (C-1, C-2). (F) The bar chart illustrates the distribution of grafted cells versus rostrocaudal distances to injection site at 4 and 8 weeks after transplantation. The number of grafted cells/distance of serial sections was expressed as a percentage of the total number of surviving cells. Values are represented as mean ± SEM.
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pone-0104092-g004: Engraftment and distribution of human NSPCs into the hippocampus of kindled rats.(A–E) Serial sections (320 µm apart) throughout the hippocampus were used to determine the location of BrdU+ grafted cells, visualized with fluorescein at 4 weeks following transplantation. A–E panels are representative images of serial coronal sections of the hippocampus which are ordered from anterior to posterior. Grafted cells had migrated apart from the injection site (arrowhead in C) and dispersed throughout the adjacent hippocampal subfields. Many grafted cells were predominantly placed in the radiatum layer (Rad) of the CA3 region, molecular (ML) and granular cell layer (GCL) of the dentate gyrus (DG), and hilus (HI) of the hippocampus. Dotted lines denote the boundary between HI and GCL of the DG. In panel C, the boxed regions of the Rad (1), and ML, GCL and HI (2) are magnified in panel C-1 and C-2, respectively. Scale bar, 500 µm (A–E) and 100 µm (C-1, C-2). (F) The bar chart illustrates the distribution of grafted cells versus rostrocaudal distances to injection site at 4 and 8 weeks after transplantation. The number of grafted cells/distance of serial sections was expressed as a percentage of the total number of surviving cells. Values are represented as mean ± SEM.

Mentions: In the kindling model, we transplanted NSPCs into the CA3 region of the right hippocampus of fully kindled rats. To evaluate the grafted cells, animals were killed at 4 and 8 weeks following transplantation, and brain tissues were processed for immunohistochemistry. BrdU+ grafted cells had migrated away from the injection site and dispersed throughout the hippocampus. Many grafted cells were predominantly located in the radiatum layer of the CA3 region, molecular and granular layer of the dentate gyrus (DG), and hilus of the hippocampus (Fig. 4A-F).


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)

Engraftment and distribution of human NSPCs into the hippocampus of kindled rats.(A–E) Serial sections (320 µm apart) throughout the hippocampus were used to determine the location of BrdU+ grafted cells, visualized with fluorescein at 4 weeks following transplantation. A–E panels are representative images of serial coronal sections of the hippocampus which are ordered from anterior to posterior. Grafted cells had migrated apart from the injection site (arrowhead in C) and dispersed throughout the adjacent hippocampal subfields. Many grafted cells were predominantly placed in the radiatum layer (Rad) of the CA3 region, molecular (ML) and granular cell layer (GCL) of the dentate gyrus (DG), and hilus (HI) of the hippocampus. Dotted lines denote the boundary between HI and GCL of the DG. In panel C, the boxed regions of the Rad (1), and ML, GCL and HI (2) are magnified in panel C-1 and C-2, respectively. Scale bar, 500 µm (A–E) and 100 µm (C-1, C-2). (F) The bar chart illustrates the distribution of grafted cells versus rostrocaudal distances to injection site at 4 and 8 weeks after transplantation. The number of grafted cells/distance of serial sections was expressed as a percentage of the total number of surviving cells. Values are represented as mean ± SEM.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0104092-g004: Engraftment and distribution of human NSPCs into the hippocampus of kindled rats.(A–E) Serial sections (320 µm apart) throughout the hippocampus were used to determine the location of BrdU+ grafted cells, visualized with fluorescein at 4 weeks following transplantation. A–E panels are representative images of serial coronal sections of the hippocampus which are ordered from anterior to posterior. Grafted cells had migrated apart from the injection site (arrowhead in C) and dispersed throughout the adjacent hippocampal subfields. Many grafted cells were predominantly placed in the radiatum layer (Rad) of the CA3 region, molecular (ML) and granular cell layer (GCL) of the dentate gyrus (DG), and hilus (HI) of the hippocampus. Dotted lines denote the boundary between HI and GCL of the DG. In panel C, the boxed regions of the Rad (1), and ML, GCL and HI (2) are magnified in panel C-1 and C-2, respectively. Scale bar, 500 µm (A–E) and 100 µm (C-1, C-2). (F) The bar chart illustrates the distribution of grafted cells versus rostrocaudal distances to injection site at 4 and 8 weeks after transplantation. The number of grafted cells/distance of serial sections was expressed as a percentage of the total number of surviving cells. Values are represented as mean ± SEM.
Mentions: In the kindling model, we transplanted NSPCs into the CA3 region of the right hippocampus of fully kindled rats. To evaluate the grafted cells, animals were killed at 4 and 8 weeks following transplantation, and brain tissues were processed for immunohistochemistry. BrdU+ grafted cells had migrated away from the injection site and dispersed throughout the hippocampus. Many grafted cells were predominantly located in the radiatum layer of the CA3 region, molecular and granular layer of the dentate gyrus (DG), and hilus of the hippocampus (Fig. 4A-F).

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