Concise review: prospects of stem cell therapy for temporal lobe epilepsy

Abstract

Certain regions of the adult brain have the ability for partial self-repair after injury through production of new neurons via activation of neural stem/progenitor cells (NSCs). Nonetheless, there is no evidence yet for pervasive spontaneous replacement of dead neurons by newly formed neurons leading to functional recovery in the injured brain. Consequently, there is enormous interest for stimulating endogenous NSCs in the brain to produce new neurons or for grafting of NSCs isolated and expanded from different brain regions or embryonic stem cells into the injured brain. Temporal lobe epilepsy (TLE), characterized by hyperexcitability in the hippocampus and spontaneous seizures, is a possible clinical target for stem cell-based therapies. This is because these approaches have the potential to curb epileptogenesis and prevent chronic epilepsy development and learning and memory dysfunction after hippocampal damage related to status epilepticus or head injury. Grafting of NSCs may also be useful for restraining seizures during chronic epilepsy. The aim of this review is to evaluate current knowledge and outlook pertaining to stem cell-based therapies for TLE. The first section discusses the behavior of endogenous hippocampal NSCs in human TLE and animal models of TLE and evaluates the role of hippocampal neurogenesis in the pathophysiology and treatment of TLE. The second segment considers the prospects for preventing or suppressing seizures in TLE using exogenously applied stem cells. The final part analyzes problems that remain to be resolved before initiating clinical application of stem cell-based therapies for TLE. Disclosure of potential conflicts of interest is found at the end of this article.

Figure 1

Changes in dentate neurogenesis following kainic acid-induced status epilepticus. Newly born neurons in the DG of a naïve adult rat (A1) and an adult rat that underwent status epilepticus 12 days prior to euthanasia (B1) were visualized with immunostaining for doublecortin, a marker of newly born neurons. (A2) and (B2) show magnified views of regions of dentate gyrus from (A1) and (B1), respectively. Note that, in comparison with the dentate gyrus of a control rat (A1, A2), a rat that underwent status epilepticus (B1, B2) exhibits considerably increased density of doublecortin⁺ new neurons and abnormal migration of newly born neurons into the dentate hilus (indicated by arrowheads in [B1]). (C1) is a magnified view of a region from (B1) showing aberrantly migrated newly born neurons in the dentate hilus. Scale bar (A1, B1) = 200 μm; (A2, B2, C1) = 50 μm. Abbreviations: DG, dentate gyrus; DH, dentate hilus; GCL, granule cell layer; SGZ, subgranular zone.

Figure 2

Distribution of doublecortin-immunopositive (newly formed) neurons in the septal and temporal regions of the chronically epileptic hippocampus. (A1): Dentate gyrus of a naïve, age-matched control rat. (B1): Dentate gyrus of a chronically epileptic rat at 5 months post-kainic acid administration. Left panel, septal hippocampus; right panel, temporal hippocampus. (A2) and (B2) are magnified views of boxed regions in (A1) and (B1). Note that the number of newly formed neurons is much less in the chronically epileptic dentate gyrus in comparison with the age-matched naïve dentate gyrus. In addition, unlike the newly formed neurons with extensive vertically oriented dendrites in the naïve dentate gyrus, newly formed neurons in the chronically epileptic dentate gyrus predominantly exhibit immature horizontally oriented or basal dendrites and less extensive vertical dendrites. Scale bar (A1, B1) = 200 μm; (A2, B2) = 50 μm. Figure reproduced from Hattiangady et al. [48]. Abbreviations: DG, dentate gyrus; DH, dentate hilus; GCL, granule cell layer; ML, molecular layer; SGZ, subgranular zone.

Figure 3

NSCs isolated from embryonic day 19 hippocampus differentiate into both larger pyramidal shaped cells that are immunopositive for TuJ-1 but lack GABA (presumably hippocampal pyramidal neurons) and interneuron-like cells that are immunopositive for both TuJ-1 and GABA (presumably GABA-ergic interneurons). (A1) shows a larger multipolar GABA immunopositive neuron (yellowish green, indicated by arrow), whereas (A2) and (A3) show smaller GABA immunopositive neurons (arrows). Note that larger neurons resembling CA3 pyramidal neurons are immunopositive for TuJ1 (red) but negative for GABA. In contrast, GABA-ergic neurons are positive for both GABA and TuJ1 and hence exhibit yellowish green color in double exposure photography. Figure reproduced from Shetty [120]. Middle panel: (B1) shows differentiation of NSCs isolated from the anterior subventricular zone into TuJ-1 positive neurons (red) and astrocytes (green). Lower panel: (C1–C3) illustrate differentiation of neurons derived from anterior subventricular zone NSCs into GABA-ergic cells. Scale bar = 25 μm. Abbreviations: E19, embryonic day 19; GABA, γ-amino butyric acid; GFAP, glial-fibrillary acidic protein; NSCs, neural stem/progenitor cells.

Figure 4

Dispersion and differentiation of BrdU-labeled NSCs isolated from the embryonic day 19 hippocampus following grafting into the lesioned hippocampal CA3 region of a kainic acid-treated rat. Note that cells derived from NSC grafts disperse extensively in the hippocampus (A1), and the graft core contains a significant number of NeuN immunopositive neurons (B1). (A2) and (B2) are magnified views of graft regions from (A1) and (B1). Panels (C1–C3) illustrate differentiation of BrdU⁺ NSCs into NeuN immunopositive neurons in the graft core (arrowheads), whereas panels (D1–D3) demonstrate neuronal differentiation of BrdU⁺ NSCs that migrated into the dentate granule cell layer (arrowheads). Scale bar (A1, B1) = 200 μm; (A2, B2) = 30 μm; (C1–D3) = 20 μm. Abbreviations: BrdU, 5′-bromodeoxyuridine; NeuN, neuron-specific nuclear antigen; NSCs, neural stem/progenitor cells; T, transplant.

Figure 5

Differentiation of grafted BrdU-labeled hippocampal neural stem/progenitor cells into GABA⁺ neurons and S-100β⁺ mature astrocytes following grafting into the lesioned hippocampal CA3 region of a kainic acid-treated rat. (A1–A3) demonstrate GABA⁺ neurons derived from grafted NSCs and (B1–B3) show S-100β⁺ astrocytes derived from grafted NSCs. Scale bar = 20 μm. Abbreviations: BrdU, 5′-bromodeoxyuridine; GABA, γ-amino butyric acid; NSCs, neural stem/progenitor cells.