Source: Derived from the inner cell mass of early-stage embryos.

Characteristics: Pluripotent, capable of differentiating into all cell types within the embryo. Although clinical use of ESCs faces scientific, ethical, and legal challenges, clinical trials utilizing human ESCs (hESCs) for therapy have commenced, with protocols established to differentiate hESCs into specialized cell types suitable for transplantation. Scientifically, precisely controlling the differentiation of ESCs into the desired neural cell types remains a complex task. The process needs to be highly regulated to ensure the production of pure populations of functional cells (37, 38). Once the limitations of ESCs are fully overcome, they may become the optimal source of stem cells.

Source: Isolated from developed tissues, such as bone marrow, adipose tissue, nervous tissue, and skin.

Characteristics: Exhibit multipotency within their tissue of origin, typically differentiating into lineage-specific cell types. Examples include bone marrow MSCs (BMSCs), neural stem cells (NSCs), and dental pulp stem cells (DPSCs) (39, 40).

Source: Generated by reprogramming somatic cells (e.g., adult fibroblasts) via genetic or epigenetic modifications to regain pluripotency (41).

Characteristics: iPSCs closely resemble ESCs in their differentiation capacity, enabling generation of cells from all three embryonic germ layers. They also possess robust self-renewal capabilities. A key advantage lies in their autologous origin, minimizing the risk of immune rejection. Additionally, iPSCs can be derived from diverse donor populations (healthy or diseased), circumventing ethical controversies associated with ESCs and broadening their clinical applicability (42–44). iPSCs have emerged as a revolutionary resource in the quest for effective stem cell therapies for epilepsy. Generated by reprogramming somatic cells, such as adult fibroblasts, through genetic or epigenetic modifications to regain pluripotency, iPSCs closely mimic ESCs in their differentiation capacity. The robust self—renewal capabilities of iPSCs further enhance their potential in epilepsy treatment. This characteristic enables the generation of large quantities of cells for transplantation, ensuring an adequate supply for clinical applications. Moreover, a key advantage of iPSCs lies in their autologous origin (45). Since iPSCs can be derived from the patient’s own cells, so the risk of immune rejection is significantly minimized (46). This is a major breakthrough compared to traditional transplantation therapies, as immune-related complications often pose significant challenges in long-term treatment success.

TSCs represent the most potent stem cell type, capable of generating all embryonic and extraembryonic cell lineages (e.g., placenta), thereby supporting the development of a complete organism (47). In the context of epilepsy, this unparalleled potency could, in theory, offer novel therapeutic strategies. However, their use raises significant ethical concerns.

PSCs can differentiate into derivatives of all three germ layers (endoderm, mesoderm, ectoderm) but lack the ability to form extraembryonic tissues (48). These cells have been adapted to in vitro culture systems distinct from their native developmental niches, facilitating their accessibility and utility in research and therapy (49).

USCs exhibit the most restricted differentiation potential and are committed to a single cell lineage (e.g., muscle satellite cells) (50). They maintain long-term self-renewal within specific tissues and differentiate to repair localized damage. Their limited ethical controversy, high safety profile, and reduced tumorigenic risk compared to PSCs make them valuable tools in regenerative medicine.

HSCs are a class of adult stem cells capable of self-renewal and differentiation into all blood cell lineages and immune cells. They serve as the foundation for the maintenance and regeneration of the hematopoietic and immune systems (51). Clinically, HSCs have been extensively utilized in the treatment of hematologic and immunologic disorders (52, 53). Despite challenges such as donor matching, transplantation-associated complications, and insufficient cell yield, advances in in vitro expansion, gene editing, and immune tolerance technologies are expected to broaden their clinical applicability. In the context of epilepsy, emerging research suggests potential roles for HSCs that extend beyond their traditional hematologic and immunologic applications. There is growing evidence of a complex interplay between the immune system and epilepsy (54).

NSCs possess the ability to differentiate into diverse cell types of the central nervous system (CNS), including neurons, astrocytes, and oligodendrocytes (55). Their differentiation potential positions NSCs as transformative agents for CNS disease therapies (56). A recent study has highlighted the therapeutic relevance of NSC-derived secretory products, which contribute to host cell survival, neuroplasticity, and neuroimmune modulation (57). In epilepsy, where there is often neuronal damage and impaired neuroplasticity, the secretory products of NSCs can play a crucial role. The paracrine mechanisms of NSCs are considered pivotal for their interaction with neural tissues, as they endogenously generate a multifaceted secretome consisting of growth factors, cytokines, chemokines, morphogens, microRNAs (miRNAs), and other bioactive molecules. For instance, miRNAs within the NSC secretome can regulate gene expression in neighboring cells, influencing processes such as cell survival, differentiation, and synaptic plasticity (58, 59). These properties underscore the immense potential of NSCs in future neurologic disease interventions. As research continues to uncover the complex interplay between NSCs and the epileptic brain, further optimization of NSC-based therapies, including the manipulation of their secretory profiles and differentiation pathways, holds great promise for effectively treating epilepsy and improving the quality of life for patients suffering from this debilitating disorder.

MSCs exhibit multipotent differentiation into mesoderm-derived lineages, such as osteocytes, chondrocytes, adipocytes, myocytes, and bone marrow stromal cells (60, 61). In the context of epilepsy, this multipotency could potentially be harnessed in novel ways. Although the primary goal in epilepsy treatment is often to correct neural dysfunctions, MSCs’ ability to differentiate into stromal cells might contribute to the creation of a more supportive microenvironment in the epileptic brain. For example, bone marrow stromal cell-like derivatives from MSCs could help in remodeling the extracellular matrix, which may be disrupted in epilepsy due to chronic seizures and associated inflammation. This remodeling could, in turn, enhance the survival and function of existing neural cells. Epilepsy is frequently associated with neuroinflammation, which can exacerbate seizure activity and contribute to neuronal damage. MSCs, with their immunomodulatory properties, could play a crucial role in mitigating this inflammation. MSCs are characterized by low immunogenicity, enabling them to suppress excessive immune responses and modulate the local immune microenvironment via secretion of cytokines and bioactive molecules, thereby attenuating inflammatory cascades (62). Preclinical studies have demonstrated that MSCs improve outcomes in animal models of neurologic disorders, including multiple sclerosis, stroke, Alzheimer’s disease, and traumatic brain injury (63). Bone marrow-derived and other tissue-specific MSCs have demonstrated favorable safety profiles in human applications (64, 65). Their versatility in administration routes—such as intravenous, intra-arterial, intraperitoneal, intrathecal, and intranasal delivery—enhances their therapeutic adaptability (66, 67). For instance, intranasal delivery of MSCs could potentially bypass the blood–brain barrier, allowing the cells to directly reach the brain tissue in a more efficient manner. This could be particularly advantageous as the blood–brain barrier may be compromised in epilepsy, but a direct and targeted method of delivery could still optimize the therapeutic effect of MSCs. MSCs are relatively accessible, with human adipose tissue serving as a robust source (68). Additionally, dental-derived MSCs can be isolated from various dental tissues (69), and OM-MSCs located in the nasal cavity have emerged as a viable source of neural stem cells (70). The ease of procurement and long-term viability of OE-MSCs render them particularly suitable for neurologic disease modeling and therapeutic development (71–74). As research progresses, further understanding of the optimal source, differentiation potential, and delivery methods of MSCs will be essential to fully realizing their potential in revolutionizing epilepsy treatment and improving the quality of life for patients suffering from this challenging neurological disorder.

Stem cells are derived from diverse sources, including ESCs, adult stem cells, and iPSCs, each possessing distinct advantages and limitations that necessitate careful selection for optimal therapeutic outcomes. Currently, MSCs have gained prominence in clinical use due to their multifaceted therapeutic properties. These include superior regenerative potential, antioxidant stress mitigation, and anti-apoptotic capabilities, which collectively contribute to their critical role in disease intervention. Moreover, MSCs exhibit remarkable secretory functions through the production of bioactive cytokines and EVs, facilitating intercellular communication and tissue repair. The relative ease of isolation from accessible tissues (e.g., adipose tissue, bone marrow, and the umbilical cord) combined with minimal ethical concerns has significantly facilitated their widespread clinical utilization (112–114). While other stem cell types demonstrate unique therapeutic potentials, their full clinical implementation requires resolution of ethical controversies and optimization of accessibility. Future advances in overcoming these challenges may unlock substantial therapeutic prospects across various stem cell platforms, enabling personalized regenerative strategies tailored to specific pathological contexts (129–131). Other stem cell types, while promising, require the addressing of ethical concerns and the overcoming of accessibility barriers to unlock their full potential.

Ensuring stem cell survival and functional integration into host neural networks post-transplantation remains a major hurdle. Key factors requiring further investigation include transplantation targets, mechanisms of action, cell types, and therapeutic outcomes (132). Key obstacles include inflammatory mediators (e.g., IL-1β, TNF-α), oxidative stress, and synaptic mismatch, which collectively impair graft viability and neural circuit integration (133). Enhancing cell survival requires strategies such as preconditioning stem cells with antioxidants (e.g., N-acetylcysteine) or genetic modifications to overexpress anti-apoptotic proteins (e.g., BCL-2). Concurrently, promoting synaptic connectivity between donor-derived neurons and host networks necessitates precise delivery timing and microenvironmental optimization, including neurotrophic support (BDNF, GDNF) and activity-dependent plasticity modulation. Critical research priorities are as follows:

Transplantation protocol optimization: Determining ideal cell types (e.g., GABAergic progenitors vs. MSCs), doses, and delivery routes (intrahippocampal vs. intravenous). Microenvironmental modulation: Utilizing biomaterials like injectable hydrogels to sustain neuroprotective factor release and shield grafts from inflammatory damage. Mechanistic clarification: Distinguishing therapeutic effects from direct synaptic integration versus paracrine signaling using optogenetic silencing and lineage-tracing technologies. Emerging tissue engineering approaches, such as 3D-printed scaffolds with topographical cues, show promise for guiding axonal growth and improving graft-host connectivity (134). Standardized metrics for evaluating therapeutic efficacy—including a reduction in seizure frequency, cognitive recovery, and functional MRI-based graft tracking—are essential for clinical translation. Future advances will require interdisciplinary efforts to address immune compatibility, long-term safety, and scalability, ultimately positioning stem cell therapy as a viable option for drug-resistant epilepsy (135).

The long-term safety profile and sustained therapeutic effects of stem cell transplantation remain incompletely characterized, necessitating rigorous longitudinal investigations to address critical knowledge gaps. Key unresolved concerns include: (1) immune-mediated rejection of allogeneic grafts, particularly in non-immunoprivileged brain regions; (2) tumorigenic potential associated with residual undifferentiated pluripotent cells; and (3) infection risks from xenogenic components in culture systems. Moreover, heterogeneity in cell sourcing (autologous vs. allogeneic) and preparation protocols (enzymatic dissociation vs. mechanical isolation) may introduce variability in clinical outcomes and safety profiles (136). Current evidence from preclinical models demonstrates sustained seizure suppression (>6 months post-transplantation) through GABAergic interneuron integration and neurotrophic modulation. However, clinical translation requires systematic evaluation of the following.

The clinical translation of stem cell therapies for epilepsy remains hindered by a critical lack of standardized protocols spanning cell selection, processing, expansion, and transplantation (132). Variability in cell sources (e.g., autologous vs. allogeneic), culture conditions, and methods of differentiation compromises both reproducibility and therapeutic reliability (137). Establishing unified industry standards is imperative to ensuring consistency in cell viability (>90%), purity (<1% undifferentiated cells), and functional potency across studies. Advances in automated, closed-system bioreactors enable scalable production of clinical-grade stem cells while minimizing contamination risks. Integration of chemically defined culture matrices and AI-driven monitoring systems further enhances batch-to-batch consistency. Collaborative efforts between regulatory bodies and scientific consortia are essential to harmonizing epilepsy-specific benchmarks, including synaptic integration capacity and subtype-specific differentiation ratios, thereby facilitating multicenter trial comparability and accelerating therapeutic validation.

Stem cell advances raise ethical, moral, and legal challenges, particularly regarding human embryo use, therapeutic cloning, and tissue sourcing. Informed consent for tissue procurement is essential to mitigating ethical disputes. Ethical debates often center on treatment risks, side effects, safety, and societal impact (138). Clinical trials must adhere to internationally recognized ethical standards, be scientifically rigorous, and adhere to principles of patient protection. These issues demand thorough consideration during research and clinical translation.

The use of stem cells in epilepsy treatment hinges on elucidating their capacity to modulate hyperexcitable neuronal networks and repair epileptogenic circuitry (139). Focal epilepsies, and particularly temporal lobe epilepsy (TLE), are characterized by hippocampal neuron loss, gliosis, and aberrant synaptic reorganization—pathological features that may be ameliorated through stem cell-derived interventions (140). Preclinical studies have highlighted the potential of MSCs to suppress neuroinflammation via anti-apoptotic and immunomodulatory cytokine secretion (e.g., TGF-β and IL-10), while iPSC-derived GABAergic interneurons may restore inhibitory tone in seizure-prone regions such as the dentate gyrus. However, challenges persist in ensuring long-term survival, targeted migration, and functional synaptic integration of transplanted cells within sclerotic hippocampi. Recent advances in optogenetic control of grafted cells and single-cell transcriptomic profiling of host-graft interactions offer novel tools to elucidate mechanisms of circuit repair (141). Further research must prioritize optimizing methods of delivery (e.g., biomaterial scaffolds for localized grafting) and mitigating risks such as ectopic cell proliferation or unintended network dysregulation (142). Further understanding of epigenetic and metabolic crosstalk between stem cells and the epileptic microenvironment will be critical to translating these therapies into clinically viable, precision-based interventions.

Large-scale, multicenter, RCTs need to be conducted to rigorously evaluate the efficacy and safety of stem cell therapy in epilepsy. Stem cell therapies are increasingly being tested in clinical trials for various conditions, such as diabetes (143–145) and neurodegenerative disorders (e.g., Parkinson’s disease, Alzheimer’s disease, and multiple sclerosis) (146–148). However, challenges persist in standardizing cell types (e.g., MSCs vs. iPSC-derived inhibitory interneurons), delivery routes (intravenous vs. intracerebral), and dosing protocols across diverse cohorts. Recent advances in epilepsy research have prompted multiple international trials assessing stem cell safety and efficacy, with preliminary results showing promise. Increasing multicenter and multinational collaboration will enhance sample diversity and enable cross-regional comparisons of therapeutic outcomes. A critical gap remains in validating objective efficacy endpoints beyond seizure diaries, such as electrophysiological biomarkers or functional neuroimaging correlates of network stabilization. Concurrently, regulatory agencies must balance accelerated approval pathways for urgent unmet needs with robust post-marketing surveillance to monitor risks like graft overgrowth or autoimmune reactions. By integrating patient-reported outcomes with mechanistic biomarkers, future trials can bridge the translational gap while maintaining ethical and scientific rigor.

In the context of epilepsy, stem cell therapy has emerged as a promising avenue for personalized treatment. Given the highly heterogeneous nature of epilepsy, with diverse etiologies and clinical manifestations among patients, a one-size-fits-all approach is often ineffective. Precision biomarkers, genetic profiling, and advanced neuroimaging can guide patient stratification, real-time monitoring of transplanted cells, and evaluation of therapeutic responses. Tailoring treatments to individual biological, genetic, and clinical profiles remains a key challenge and opportunity for improving outcomes (149). Precision biomarkers, such as seizure-associated miRNA profiles or PET/MRI-based metabolic signatures, could further stratify patients for autologous vs. allogeneic cell therapies and track graft viability post-transplantation (150). Genetic profiling is another essential tool. Epilepsy is known to have a significant genetic component, and different genetic mutations can lead to distinct pathophysiological mechanisms. Through comprehensive genetic profiling, researchers can determine the genetic background of a patient’s epilepsy. This knowledge can then be used to engineer stem cells that are genetically modified to correct the underlying genetic defects. However, tailoring stem cell treatments to individual biological, genetic, and clinical profiles is not without challenges. The complexity of the epileptic brain, with its multiple interacting neural networks and compensatory mechanisms, hampers the precise prediction of how the transplanted stem cells will behave.

In the pursuit of effective stem cell therapies for epilepsy, emerging technologies are playing a transformative role. CRISPR-based gene editing has emerged as a powerful tool with immense potential. Epilepsy is often associated with various genetic mutations, and CRISPR technology allows for the precise targeting and correction of these epilepsy-associated genetic defects (151). By modifying the genetic code within stem cells, researchers can potentially create cells that are resistant to abnormal neural firing patterns characteristic of epilepsy (152). If, for example, a specific gene mutation is causing an over-excitability of neurons in the epileptic brain, CRISPR can be used to edit the gene to restore normal neuronal function. This not only holds promise for treating the underlying cause of epilepsy but also for enhancing the therapeutic properties of stem cells, making them more effective in suppressing epileptic seizures. Single-cell genetic reprogramming techniques are also revolutionizing the field. These techniques enable scientists to exercise precise control over stem cell differentiation and function. In the context of epilepsy treatment, this means the ability to generate specific types of neural cells that can integrate seamlessly into the epileptic brain and restore normal neural circuitry (153). For instance, precisely reprogramming stem cells at the single-cell level enables the creation of inhibitory neurons, which are often deficient in epileptic brains. These inhibitory neurons can then be transplanted into the epileptic focus to counterbalance the excessive excitatory activity, potentially halting seizure propagation. This targeted approach, made possible by single-cell genetic reprogramming, offers a novel cell source for epilepsy treatment that was previously unattainable. Advances in cell processing and methods of transplantation are equally crucial. Biomaterial scaffolds, for example, can provide a supportive framework for transplanted stem cells. In the epileptic brain, which has a complex and often damaged neural environment, these scaffolds can help guide the migration and integration of stem cells to the appropriate regions (154). They can also mimic the natural extracellular matrix, promoting cell survival and differentiation. Combining these innovative cell processing and transplantation techniques will enable the safety and effectiveness of stem cell therapies for epilepsy to be significantly enhanced, bringing us closer to a viable treatment option for this challenging neurological disorder.

Combining stem cell therapy with existing treatments—such as AEDs, the ketogenic diet (KD), or neuromodulation—may yield synergistic benefits. AEDs are currently the cornerstone of epilepsy treatment, aiming to control seizure frequency and severity (155). However, a significant proportion of patients remain refractory to these medications. Stem cell therapy, with its potential to modulate the epileptic brain at a cellular and molecular level, could complement AEDs. The KD, a high-fat, low-carbohydrate regimen for drug-resistant epilepsy, modulates biochemical pathways to reduce seizures (156). The KD increases the production of ketone bodies, which can act as an alternative energy source for the brain. In the context of epilepsy, this metabolic shift may also have a direct impact on neuronal excitability. Investigating its synergy with stem cell therapy could enhance efficacy. Stem cells, when transplanted, might respond to the altered metabolic environment induced by the KD. For instance, the increased availability of ketone bodies could potentially facilitate the survival and differentiation of transplanted stem cells into functional neural cells, thereby enhancing their overall anti-epileptic effect (157). Investigating its synergy with stem cell therapy could enhance efficacy. Similarly, integrating stem cell grafts with deep brain stimulation (DBS) targeting the anterior nucleus of the thalamus (ANT) may offer novel strategies for drug-refractory epilepsy (158). This multi-modal approach holds great promise for improving treatment outcomes for patients with drug-refractory epilepsy.

Establishing robust ethical and legal guidelines is essential to ensuring compliance and protecting patient rights. Transparent reporting of clinical trial data, public disclosure of research protocols, and rigorous oversight will foster trust and standardization. As regulations evolve, stem cell research and use of those cells in epilepsy must align with international ethical standards, balancing innovation with societal and moral considerations.