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.
Highlights
Epilepsy is a chronic neurological disorder affecting tens of millions of people worldwide, and more than 30% of patients with epilepsy still have uncontrolled seizures despite conventional antiepileptic drugs (AEDs) [1]
We investigated whether epileptic phenotypes could be improved in both kindling and pilocarpineinduced Temporal lobe epilepsy (TLE) models by human fetal brain-derived neural stem/ progenitor cell (NSPC) grafts into the hippocampus after epileptic seizures emerged, and characterized the distribution, engraftment, and the differentiation patterns of cells implanted in adult recipients
At 7 days after plating of neurosphere-derived single cells under differentiation conditions,61% of NSPCs had differentiated into TUJ1+ neurons,2% into platelet-derived growth factor receptor alpha (PDGFR-a)+ oligodendrocyte progenitors, and,5% into glial fibrillary acidic protein (GFAP)+ astrocytes (Fig. 1J)
Summary
Epilepsy is a chronic neurological disorder affecting tens of millions of people worldwide, and more than 30% of patients with epilepsy still have uncontrolled seizures despite conventional antiepileptic drugs (AEDs) [1]. Over the past few years, embryonic stem cell (ES)-, neural stem cell (NSC)-, or neural precursor-based approaches have been examined in animal models of epilepsy: mouse ES-derived neural precursors in pilocarpine- or kainic acid-induced status epilepticus (SE) or kindling-based TLE models [12,13,14,15], rat fetal ganglionic eminence (GE)-derived neural precursors or NSC in the kainic acid-induced TLE model [16,17], mouse fetal neural precursors from the medial ganglionic eminence (MGE) in congenital general epilepsy or pilocarpine-induced adult TLE models [18,19], and immortalized human fetal brain-derived NSC in the pilocarpine-induced SE model [20] These studies have demonstrated that neural stem/ progenitor cell (NSPC)-based therapies in acute and chronic models of epilepsy exert anticonvulsant and antiepileptogenic effects, and may replace degenerated or ablated neurons and repair damaged neural circuitry [7,9,10,11]
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