Seizure Suppression in Amygdala-Kindled Mice by Transplantation of Neural Stem/Progenitor Cells Derived From Mouse Embryonic Stem Cells

Abstract

Embryonic stem cells (ES cells) differentiate into multiple cell lineages including neural cells. The present study optimized the method to induce differentiation of gamma-aminobutyric acid-producing neurons (GABAergic neurons) from ES cell-derived neural stem/progenitor cells (NS/PCs), and transplanted these ES cell-derived GABAergic neurons producing neural progenitors into kindled epileptic mice, and analyzed the morphological and functional recovery from epilepsy. The response of kindling was evaluated by the modified Racine scale. Following stage 5 kindling, the mice were divided into two groups. Group 1 received NS/PCs derived from the ES cells ubiquitously expressing green fluorescent protein transplanted into the dorsal hippocampal area. Group 2 received microinjections of only the medium. After transplantation, the recovery of seizures was evaluated by the modified Racine scale again. All mice were perfused and fixed for immunohistochemical analysis after finishing the kindling experiment. In Group 1, one mouse was classified as stage 0, five as stage 3, and one as stage 4 recovering from stage 5 at 6 weeks after transplantation. In Group 2, all mice remained in stage 5. The transplanted cells were examined immunohistochemically using neuronal and GABAergic markers. In the transplanted mice, substantial hippocampal GABAergic re-innervation and seizure-suppressing effects were observed. NS/PCs derived from ES cells have high potential for use in transplantation therapy for clinically intractable epilepsies.

Progress in Cell Grafting Therapy for Temporal Lobe Epilepsy

“…The reasons for using NSC grafting therapy for suppressing SRS in TLE include their ability to: 1) migrate profusely into different cell layers of the hippocampus, 2) give rise to a sizable fraction of neurons synthesizing the inhibitory neurotransmitter GABA, and 3) generate astrocytes secreting the anticonvulsant factors such as the glial-derived neurotrophic factor (GDNF) [37,74,75]. In addition, NSC grafting has promise for easing cognitive and mood dysfunction seen in TLE, as NSCs can be a source of multiple neurotrophic factors that are capable of increasing the proliferation of endogenous NSCs and boosting the extent of net hippocampal neurogenesis [76], one of the substrates believed to be important for maintaining the hippocampal-dependent cognitive function and mood [77][78][79][80][81].…”

“…However, additional strategies for improving: 1) the yield of graft-derived GABA-ergic neurons, 2) the overall seizure suppression; and 3) the hippocampal neurogenesis and cognitive function, will need to be developed prior to any clinical application of this strategy. Efficacy of ES Cell-Derived NSC Grafts for Easing Chronic TLE A recent study has examined the effectiveness of grafting NSCs originated from the mouse ES cells into the hippocampus of kindled epileptic mice displaying the stage V seizures for controlling SRS [75]. Assessment of SRS at 6 weeks following the grafting through behavioral surveillance revealed a partial recovery from seizures in all animals that received NSC grafts.…”

GABAergic Neuronal Precursor Grafting: Implications in Brain Regeneration and Plasticity

“…More recently, Shindo et al [56] optimized a method to induce differentiation of GABAergic neurons from ESNP, and transplanted them into kindled epileptic mice to analyze a possible morphological and functional recovery. Two weeks after transplant, they observed a partial recovery of seizures.…”

Human Fetal Brain-Derived Neural Stem/Progenitor Cells Grafted into the Adult Epileptic Brain Restrain Seizures in Rat Models of Temporal Lobe Epilepsy

“…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]–[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]–[11].…”