Stem cell repair strategies for epilepsy

Abstract

Epilepsy is a serious neurological disorder; however, the effectiveness of current medications is often suboptimal. Recently, stem cell technology has demonstrated remarkable therapeutic potential in addressing various neurological diseases, igniting interest in its applicability for epilepsy treatment. This comprehensive review summarizes different therapeutic approaches utilizing various types of stem cells. Preclinical experiments have explored the use and potential therapeutic effects of mesenchymal stem cells, including genetically modified variants. Clinical trials involving patient-derived mesenchymal stem cells have shown promising results, with reductions in the frequency of epileptic seizures and improvements in neurological, cognitive, and motor functions reported. Another promising therapeutic strategy involves neural stem cells. These cells can be cultured outside the body and directed to differentiate into specific cell types. The transplant of neural stem cells has the potential to replace lost inhibitory interneurons, providing a novel treatment avenue for epilepsy. Embryonic stem cells are characterized by their significant capacity for self-renewal and their ability to differentiate into any type of somatic cell. In epilepsy treatment, embryonic stem cells can serve three primary functions: neuron regeneration, the maintenance of cellular homeostasis, and restorative activity. One notable strategy involves differentiating embryonic stem cells into γ-aminobutyric acidergic neurons for transplantation into lesion sites. This approach is currently undergoing clinical trials and could be a breakthrough in the treatment of refractory epilepsy. Induced pluripotent stem cells share the same genetic background as the donor, thereby reducing the risk of immune rejection and addressing ethical concerns. However, research on induced pluripotent stem cell therapy remains in the preclinical stage. Despite the promise of stem cell therapies for epilepsy, several limitations must be addressed. Safety concerns persist, including issues such as tumor formation, and the low survival rate of transplanted cells remains a significant challenge. Additionally, the high cost of these treatments may be prohibitive for some patients. In summary, stem cell therapy shows considerable promise in managing epilepsy, but further research is needed to overcome its existing limitations and enhance its clinical applicability.

Keywords: astrocyte transdifferentiation; cell therapy; cell transplantation; clinical trials; embryonic pluripotent stem cells; epilepsy; gamma-aminobutyric acidergic neuron; induced pluripotent stem cells; mesenchymal stem cells; nerve regeneration; neural stem cells; organoid.

Figure 1

A pie chart overview of mechanisms of stem cell therapy for epilepsy. Mesenchymal stem cells primarily exert their therapeutic effects through nutritional support, producing extracellular vesicles and growth factors. Preclinical and clinical trials have demonstrated that patient-derived mesenchymal stem cells can reduce seizure frequency. Neural stem cells secrete neurotrophic factors such as brain-derived neurotrophic factor and glial cell line derived neurotrophic factor, possess immunomodulatory effects, and can be directed to differentiate into specific cell types in vitro. Transplanting neural stem cells can replace lost inhibitory interneurons, offering a potential treatment for epilepsy. Embryonic stem cells exhibit remarkable self-renewal and differentiation potential, enabling neuron regeneration, the maintenance of cellular homeostasis, and restorative therapies. Differentiating embryonic stem cells into γ-aminobutyric acidergic neurons for transplantation is a promising strategy in clinical trials for refractory epilepsy. Induced pluripotent stem cells, sharing the same genetic background as the donor, reduce immune rejection and ethical concerns. They allow for the creation of patient-specific neurons for disease modeling and drug testing. Additionally, induced pluripotent stem cells-derived organoids are revolutionizing regenerative medicine, while research into astrocyte reprogramming shows potential but remains controversial. Created with BioRender.com.

Figure 2

A timeline outlining key milestones in the development of therapies for epilepsy with a focus on DRE and stem cell treatment. The recognition of drug resistance as a significant challenge marked a turning point in epilepsy treatment. Since then, research has explored the potential of various types of stem cells. Clinical trials have assessed the safety and efficacy of mesenchymal stem cells in treating DRE. The timeline highlights the progress in this field, underscoring the promising role of ESCs in advancing epilepsy therapy. Created with BioRender.com. DRE: Drug-resistant epilepsy; ESCs: embryonic stem cells.

Figure 3

Stem cell therapy for epilepsy. This image illustrates various types of stem cells used in the treatment of epilepsy. The stem cells depicted include neural stem cells, mesenchymal stem cells derived from bone marrow or adipose tissue, embryonic stem cells extracted from the endoderm, and induced pluripotent stem cells reprogrammed from vascular endothelial cells and fibroblasts. Stem cell therapy has shown promising results in animal models for epilepsy treatment and is gradually advancing to clinical trials. Created with BioRender.com.

Figure 4

The process of differentiation of embryonic and induced pluripotent stem cells for epilepsy. This image illustrates the process by which embryonic stem cells and induced pluripotent stem cells differentiate into neurons for the treatment of epilepsy. Initially, these stem cells aggregate to form embryoid bodies. They then differentiate into neuroepithelial stem cells with a rosette structure through induction and ultimately develop into GABAergic neurons, which play an antiepileptic role when transplanted into the hippocampus. In preclinical studies, these cells have demonstrated significant antiepileptic effects following hippocampal transplantation (Bershteyn et al., 2023; Zhu et al., 2023). This innovative treatment approach has shown promising results and has now advanced to clinical Phase 1/2 trials. Created with BioRender.com. GABA: γ-Aminobutyric acid.

Figure 5

In situ reprogramming of astrocytes into GABAergic neurons for the treatment of epilepsy. This image illustrates that the directional injection of neurotranscription factors, such as Ascl1, Dlx2, and NeuroD1, into the brain can reprogram hyperactive astrocytes in situ into GABAergic neurons. This process effectively inhibits seizures. Created with BioRender.com. Ascl1: Achaete-scute complex like 1; Dlx2: distal-less homeobox 2; GABA: γ-aminobutyric acid; NeuroD1: neurogenic differentiation 1.