Abstract
Epilepsy is a common disabling chronic neurological disorder characterized by an enduring propensity for the generation of seizures that result from abnormal hypersynchronous firing of neurons in the brain. Over 20–30% of epilepsy patients fail to achieve seizure control or soon become resistant to currently available therapies. Prolonged seizures or uncontrolled chronic seizures would give rise to neuronal damage or death, astrocyte activation, reactive oxygen species production, and mitochondrial dysfunction. Stem cell therapy is potentially a promising novel therapeutic strategy for epilepsy. The regenerative properties of stem cell-based treatment provide an attractive approach for long-term seizure control, particularly in drug-resistant epilepsy. Embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), neural stem cells (NSCs), induced pluripotent stem cells (iPSCs), and adipose-derived regenerative cells (ADRCs) are capable of differentiating into specialized cell types has been applied for epilepsy treatment in preclinical animal research and clinical trials. In this review, we focused on the advances in stem cell therapy for epilepsies. The goals of stem cell transplantation, its mechanisms underlying graft effects, the types of grafts, and their therapeutic effects were discussed. The cell and animal models used for investigating stem cell technology in epilepsy treatment were summarized.
Introduction
Epilepsy is a spectrum of heterogenous chronic brain disorders characterized by an enduring propensity for the generation of seizures which are the recurrent abnormal and hypersynchronous firing of neurons from dysfunctional brain circuits. Epilepsy remains one of the most prevalent neurological conditions affecting approximately 50–60 million people worldwide (WHO, ). Epilepsy can be classified into three major categories based on the possible underlying etiologies: idiopathic (genetic), symptomatic (acquired) including structural, infectious, metabolic, and immune etiologies, as well as unknown/cryptogenic (presume symptomatically) (Engel, ; Scheffer et al., ). Pharmacological therapy is the mainstay of treatment for epilepsy and many new anti-seizure medications (ASMs) have been developed in the past decades (Galanopoulou et al., ; Loscher, ). However, nearly one-third of epilepsy patients still fail to achieve seizure control or soon become resistant to currently available therapies (Kwan and Brodie, , ; Shorvon, ,). Presently available medications are based on symptomatic strategies aiming to suppress or reduce the frequency and severity of seizures. These approaches do not affect and modify the underlying processes of epilepsy (Galanopoulou et al., ; Loscher et al., ). There is an unmet need to develop a therapeutic strategy for epilepsy that more specifically targets dysfunctional epileptic circuitry, particularly for medically refractory epilepsy and for suppressing the development and progression of epilepsy.
Stem cells are “undifferentiated” cells that have not yet engaged in a developmental path to form a specific cell type or tissue. These cells have the potential to be differentiated into a variety of specialized post-mitotic cell lineages (Kolios and Moodley, ). Stem cells can be classified into four major categories according to their origins: (1) Embryonic stem cells (ESCs), (2) Infant stem cells such as umbilical cord stem cells, (3) Adult stem cells (ASCs) including tissue-resident stem cells (e.g. ectoderm), neural stem cells, mesenchymal stem cells (MSCs) which can be obtained from bone marrow and adipose tissue, and (4) induced pluripotent stem cells (iPSCs) which are genetically reprogrammed adult stem cells to exhibit characteristics of ESCs (Fortier, ; Kolios and Moodley, ; EL Barky et al., ). These stem cells possess different differentiation potencies that are totipotent, pluripotent, multipotent, unipotent, and oligopotent cells (EL Barky et al., ). Totipotent cells have the capacity to differentiate into any cell type, form any tissue and produce an entire organism. Pluripotent cells have the potential to give rise to nearly all cells containing the three germ layers of the embryo, endoderm, mesoderm, and ectoderm. Multipotent cells can restrictedly differentiate to cell types related to their origin tissues. Unipotent cells and oligopotent cells can only be specialized in limited cell lineages of their own kind (EL Barky et al., ). As stem cells have the ability of self-replication and transform into specialized cell types, they play an important role in tissue repair and regeneration and provide the potential to restore and integrate the dysfunctional brain circuits to a normal state.
The therapeutic use of various stem cell types for the treatment of epilepsy has been increasingly explored in experimental and clinical research (Table 1). The pathophysiological mechanisms of epilepsy are attributed to a dysfunctional receptor or molecule expression of neural cells within the brain, neuronal damage or loss, astrocyte activation, reactive oxygen species production, and mitochondrial dysfunction. Stem cell-based treatment provides an attractive approach for replacement of the damaged or lost cells, correcting the imbalance of excitatory and inhibitory electrical activity in epileptic focus and brain circuits. Growing studies show that stem cell transplantation therapy is a novel promising therapeutic strategy for epilepsy. In this review, we focus on recent advancements in stem cell therapy for epilepsies and discuss the potential mechanisms, various graft sources, and their effects. We also review the disease models used for studying stem cell technology in epilepsy treatment.
Table 1
| Type of stem cells | Animal model or clinical trail | Route of administration | Conclusion | References |
|---|---|---|---|---|
| Rat ADK-deficient ESC-derived NPs | Electrically-induced status epilepticus rat model | Intracerebral grafting into hippocampi | Retardation of epileptogenesis and prevented the occurrence of generalized seizures | Li et al., |
| ESCs-derived EMG | Transgenic rodent model | Intracerebral injection into cortex | Reduction of the duration and frequency of spontaneous electrographic seizures | Baraban et al., ; Hammad et al., |
| ESCs-derived EMG | Rodent model | Intracerebral grafting into hippocampi | Reduced electrographic seizures and improved spatial learning, hyperactivity and aggressive response | Hunt et al., ; Casalia et al., |
| hESCs | Rodent model | Intracerebral grafting into hippocampi | Decreased the frequency and duration of spontaneous recurrent seizures | Waloschkova et al., |
| NSCs | Rodent model | Intravenous infusion | Histopathological analysis displayed alleviation of oxidative damage | de Gois da Silva et al., |
| NSCs | Rodent model | Intracerebral grafting into hippocampi | Decreased the frequency and duration of spontaneous recurrent seizures | Xu et al., ; Lentini et al., |
| NSCs | Rodent model | Intracerebral grafting into hippocampi | Restrained epileptogenesis, and decreased the frequency and duration of spontaneous recurrent seizures. Reduced cognitive and mood impairments | Hattiangady et al., |
| MSCs | Rodent model | Intravenous infusion | Mitigated epileptogenesis and preserved cognitive function | Fukumura et al., ; Ali et al., |
| Adipose-derived MSCs | Rodent model | Intracerebral transplanting into hippocampus | Alleviated EEG burst and improved learning and memory function | Wang et al., |
| Autologous bone marrow mononuclear-derived MSCs | Clinical trial | Intravenous and intrathecal injection | Safe and significantly reduced seizure frequency, and have unique immunomodulatory properties | Hlebokazov et al., , |
| Autologous bone marrow- derived MSCs | Clinical trial | Intravenous and intrathecal injection | Mitigated seizure frequency, improved cognitive function and no adverse events. | Milczarek et al., |
| Autologous bone marrow- derived MSCs | Clinical trial | Intra-arterial infusion | 40% patient seizure free at six months follow up, and significant memory improvement | DaCosta et al., |
| Autologous bone marrow- derived MSCs | Clinical trial | Intravenous injection | Remission of seizure activity in 65% of patients | Hammadi, |
| Autologous adipose-derived MSCs | Clinical trail | Intrathecal infusion | Seizure free in only 1 of 6 patients, and unsatisfactory seizure reduction or no apparent remission in others | Szczepanik et al., |
| hiPSCs | Rodent model | Intracerebral grafting into hippocampi | Reduced seizure activity and ameliorated memory impairment, hyperactivity and aggressive behaviors | Cunningham et al., ; Upadhya et al., |
Preclinical and clinical studies of stem cell therapy for epilepsy.
ADK, adenosine kinase; ESCs, Embryonic stem cells; hESCs, human embryonic stem cells; NSCs, Neural stem cells; NPs, Neuronal precursor cells; MSCs, Mesenchymal stem cells; hiPSCs, human induced pluripotent stem cells.
Mechanisms of Action of Neurotransplantation for Epilepsy
The fundamental pathophysiologic basis of epilepsy is the transformation of the brain from a normal neuronal network to a long-lasting hyperexcitable state owing to an imbalance between the excitatory neurons and inhibitory neurons in the brain. Theoretically, stem cell transplantation could have disease-modifying effects to restore the malfunction of the epileptic brain via diverse mechanisms including specific cell substitution, rescue and repair of degeneration cells, reorganization of synapses, modulation of the secretion of neurotransmitters or beneficial neurotrophic factors (Li et al., ; Roper and Steindler, ; Hattiangady et al., ).
Cell Substitution
Epilepsy is often associated with either programmed or unprogrammed cell death. Replacement of damaged and lost cells or specific cell lines such as implantation of GABAergic interneurons integrating into pre-existing brain circuitry to achieve the suppression of hyperexcitation of neural networks (Waldau et al., ; Shetty and Upadhya, ).
Cell Rescue
The regenerative properties of grafted stem cells are capable to ameliorate host cells from the degenerative processes, repair myelin sheaths of axons in the impaired neurons and enhance neurogenesis, and restrain anomalous mossy fiber sprouting in the epileptic brain (Uchida et al., ; Kodali et al., ; Hattiangady et al., ). Stem cells also exhibit neuroprotective capacity by attenuating oxidative stress and glutamate excitotoxicity associated with epilepsy (de Gois da Silva et al., ; Papazian et al., ; Luo et al., ).
Supplement of Beneficial Neurotrophic Factors
Grafted stem cells can differentiate into glial cells which have an important role in secreting many neurotrophic factors and molecules including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), insulin-like growth factor-1 (IGF-1) and microRNA to support neuron survival, neurogenesis and maintain normal neuronal function (Waldau et al., ; Lai et al., ; Ali et al., ; Hattiangady et al., ; Wang et al., ).
Anti-Inflammatory Properties
MSCs and NSCs could suppress the neuroinflammation process via inhibiting the secretion of proinflammatory factors and promoting the release of anti-inflammatory factors, as well as modulate neuroimmune responses through direct cell contact (Ryu et al., ; Cao et al., ; Wang et al., ; Kim et al., ).
Therapeutic Applications and Effects of Stem Cells in Epilepsy
The utility of in vitro stem cell technology by patient-derived iPSCs to high-throughput screening of anti-seizure medications can be applied for personalized epilepsy therapy (Jiao et al., ; Kaufmann et al., ; Elitt et al., ; Lybrand et al., ). The potential major roles of stem cell therapy in epilepsy are seizure remission, inhibition of the progression of the epileptogenic process, prophylaxis against the development of chronic epilepsy, and improvement of cognitive function (Aligholi et al., ; Sadanandan et al., ; Ramos-Fresnedo et al., ). A phase I clinical trial study showed a favorable seizure reduction, a good safety profile, and improvement of pathological hallmarks in epilepsy patients treated with autologous MSCs (Hlebokazov et al., ).
Sources and Types of Stem Cells
The pathogenesis of epilepsy is not only limited to dysfunction of neurons (such as glutamatergic and GABAergic cells) but also involves glia such as astrocytes and microglia. Various sources and many types of cells have been tested as a novel treatment in epilepsy to explore the therapeutic potency and safety of stem cell therapy, particularly for drug-resistant epilepsy.
Embryonic Stem Cells (ESCs)
Embryonic stem cells are pluripotent that can be differentiated into almost any cell lineage. Cortical inhibitory interneurons mainly originate from the embryonic medial and caudal ganglionic eminences in the forebrain during development (Wichterle et al., ; Xu et al., ; Butt et al., ). Grafting medial ganglionic eminence (MEG) progenitors into the brain exhibits normal migratory activity and can functionally differentiate as GABAergic inhibitory neurons and integrate into the neural circuitry to suppress seizures (Baraban et al., ; Hunt et al., ; Casalia et al., ). However, transplantation of rodent embryonic caudal ganglionic eminence (CGE) was not shown a reduction in seizure activity (Casalia et al., ). Despite the embryonic stem cells owning a great differentiation capacity to various cell types, the ethical concerns limit the utility of embryonic stem cells harvested from humans for stem cells.
Neural Stem Cells (NSCs)
Neural stem cells are multipotent cells capable of self-renewing and generating three major cell types of the central nervous system: neurons, astrocytes, and oligodendrocytes (Al-Mayyahi et al., ). In the adult brain, only two regions have the ability of neurogenesis: the subventricular zone of the lateral ventricle and the subgranular zone of the hippocampal dentate gyrus (Parent et al., ; Miltiadous et al., ). NSCs can be harvested from several sources such as fetal, postnatal, and adult brains, and also can be generated from ESCs and iPSCs (Hattiangady and Shetty, ; Noebels et al., ). In the animal model of temporal lobe epilepsy, transplanting NSCs into the hippocampus appears responsive effects on seizure remission and has the potential to mitigate and repair epilepsy-induced pathological changes (Hattiangady and Shetty, ; Noebels et al., ; Uchida et al., ; de Gois da Silva et al., ; Xu et al., ). While NSCs show promising potential for treating mesial temporal lobe epilepsy, clinical research is paucity and a lack of data to demonstrate the effectiveness of NSC therapy on other forms of epilepsy.
Mesenchymal Stem Cells (MSCs)
Mesenchymal stem cells are multipotent cells that can be isolated from bone marrow, adipose tissue, umbilical cord blood, placenta, and amniotic fluid (Kolios and Moodley, ; Berebichez-Fridman and Montero-Olvera, ). MSCs possess self-renewal capacities and are able to differentiate into many specialized cell types including neurons (Tropel et al., ). Recently, several preclinical animal and clinical studies have investigated the applications of MSCs for the treatment of epilepsy and appear potentials to ameliorate the severity of epilepsy and attenuate epilepsy-induced excitotoxicity, oxidative stress, and neuroinflammation (Fukumura et al., ; Milczarek et al., ; Papazian et al., ; Kodali et al., ; Xian et al., ; Linares et al., ). Furthermore, stem cell therapy using MSCs allows either allogeneic or autologous transplantation that extends the clinical feasibility. Clinical trials with autologous MSCs obtained from human bone marrow or adipose-derived regenerative cells for the treatment of medically refractory epilepsy display variable efficacy of seizure reduction with the improvement of cognitive and psychomotor function and good safety of the therapy (Hlebokazov et al., ; Milczarek et al., ; Szczepanik et al., ).
Induced Pluripotent Stem Cells (iPSCs)
Induced pluripotent stem cells can be non-invasively derived from adult somatic cells such as fibroblast or peripheral mononuclear blood cells undergoing genetic reprogramming to have pluripotent properties (Yu et al., ; Braganca et al., ). iPSCs are able to differentiate into many neural cell types including distinct subtypes of GABAergic interneurons, astrocytes, motor neurons, and Purkinje cells (Du and Parent, ; Wang et al., ; Watson et al., ). Specific cell types derived from iPSCs implanting into the epileptic brain can migrate extensively into different subfields of the target brain region with synaptic integration of grafted cells into the dysfunctional circuitry (Cunningham et al., ). Grafting maturing GABAergic interneurons derived from human-induced pluripotent stem cells (hiPSCs) in an epilepsy mouse model has been shown to mitigate seizures and improve cognitive function, aggressive behavior, and mood (Cunningham et al., ). Implanting hiPSCs-derived MGE-like interneuron precursors into epileptic rodent hippocampi showed anti-epileptic and anti-epileptogenic effects with significantly restraining seizure phenotypes and alleviating cell loss, abnormal neurogenesis, and aberrant mossy fiber sprouting (Noakes et al., ; Upadhya et al., ). Nonetheless, there is still a lack of clinical data showing the application of iPSCs for the treatment of human epilepsy.
Disease Models and Animal Model Studies
Use of iPSCs to Model Diseases
Patient-derived iPSCs are models of a patient's genetic background and can be used as a platform for modeling patient-specific diseases, human genetic epilepsies, high throughput drug screening, and studying the mechanisms of epilepsy (Sun et al., ; Elitt et al., ; Kim et al., ).
Stem Cell Transplants in Animal Models of Epilepsy
Mesial temporal lobe epilepsy (mTLE) which mainly involves the hippocampus is often medically refractory. Animal models mimic mesial temporal lobe epilepsy including kainic acid and pilocarpine rodent models are commonly used in chronic epilepsy models for stem cell research (Cunningham et al., ; Casalia et al., ; Upadhya et al., ; Lentini et al., ; Waloschkova et al., ). Electrically-induced status epilepticus model is another applicable rodent model of status epilepticus and chronic mTLE (Li et al., ). Genetic or transgenic mice such as Kv1.1 mutation which associates with human episodic ataxia type 1 and focal cortical epilepsy, and Stargazer (stg) transgenic mouse model of absence epilepsy have been applied to explore the therapeutic effects on epilepsy by transplantation of GABAergic interneurons into the brain (Baraban et al., ; Hammad et al., ). Pentylenetetrazole and picrotoxin rodent models are acute seizure models that can be used to evaluate the anticonvulsant effects of cell-based therapy (Handreck et al., ; de Gois da Silva et al., ).
Perspectives of Clinical Application of Neurotransplantation of iPSCs for Epilepsy
iPSCs obtained from patients themselves can be manipulated or corrected by novel genetic editing technology such as CRISPR/Cas9, then autologously implanted into patients to repair their underlying pathological circuits in the epileptic brain (Hockemeyer and Jaenisch, ; Dever et al., ). Combining the iPSCs and genetic engineering technology might serve as a potential disease-modifying treatment for epilepsy and personalized therapy.
Conclusions
Emerging evidence suggests that stem cell approaches could be a promising tool in epilepsy treatment. However, further studies are required to investigate and address the optimal regimen, microenvironment, and timing of stem cell differentiation and implantation. In addition, compared to ESCs and NSCs, MSCs and iPSCs do not raise ethical issues. Autologous cell transplants avoid the immune response and have better integration between the graft and host cells which would be a good option for the development of cell-based therapy. Advanced preclinical investigations in clinically relevant models of epilepsy and larger clinical trials need to be conducted to further demonstrate the efficacy and safety of stem cell therapy for epilepsy.
Funding
This work was supported by grants from Chang Gung Memorial Hospital, Taipei, Taiwan (CMRPG3I0521, CMRPG3K1021, CMRPG3L0661, and BMRPJ26) and the Ministry of Science and Technology, Taiwan (MOST 108-2314-B-182A-153 -, MOST 109-2314-B-182-079-, and MOST 110-2314-B-182-055-).
Publisher's Note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
Statements
Author contributions
B-LC: conceptualization and funding acquisition. B-LC and K-HC: writing—original draft and writing—review and editing. Both authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
References
1
AliS. O.ShahinN. N.SafarM. M.RizkS. M. (2019). Therapeutic potential of endothelial progenitor cells in a rat model of epilepsy: role of autophagy. J. Adv. Res.18, 101–112. 10.1016/j.jare.2019.01.013
2
AligholiH.SafahaniM.Asadi-PooyaA. A. (2021). Stem cell therapy in patients with epilepsy: a systematic review. Clin. Neurol. Neurosurg.200, 106416. 10.1016/j.clineuro.2020.106416
3
Al-MayyahiR. S.SterioL. D.ConnollyJ. B.AdamsC. F.Al-TumahW. A.SenJ.et al. (2018). A proteomic investigation into mechanisms underpinning corticosteroid effects on neural stem cells. Mol. Cell Neurosci.86, 30–40. 10.1016/j.mcn.2017.11.006
4
BarabanS. C.SouthwellD. G.EstradaR. C.JonesD. L.SebeJ. Y.Alfaro-CervelloC.et al. (2009). Reduction of seizures by transplantation of cortical GABAergic interneuron precursors into Kv1.1 mutant mice. Proc. Natl. Acad. Sci. U.S.A.106, 15472–15477. 10.1073/pnas.0900141106
5
Berebichez-FridmanR.Montero-OlveraP. R. (2018). Sources and clinical applications of mesenchymal stem cells: state-of-the-art review. Sultan Qaboos Univ. Med. J.18, e264–e277. 10.18295/squmj.2018.18.03.002
6
BragancaJ.LopesJ. A.Mendes-SilvaL.Almeida SantosJ. M. (2019). Induced pluripotent stem cells, a giant leap for mankind therapeutic applications. World J. Stem Cells11, 421–430. 10.4252/wjsc.v11.i7.421
7
ButtS. J.FuccilloM.NeryS.NoctorS.KriegsteinA.CorbinJ. G.et al. (2005). The temporal and spatial origins of cortical interneurons predict their physiological subtype. Neuron48, 591–604. 10.1016/j.neuron.2005.09.034
8
CaoW.YangY.WangZ.LiuA.FangL.WuF.et al. (2011). Leukemia inhibitory factor inhibits T helper 17 cell differentiation and confers treatment effects of neural progenitor cell therapy in autoimmune disease. Immunity35, 273–284. 10.1016/j.immuni.2011.06.011
9
CasaliaM. L.HowardM. A.BarabanS. C. (2017). Persistent seizure control in epileptic mice transplanted with gamma-aminobutyric acid progenitors. Ann. Neurol.82, 530–542. 10.1002/ana.25021
10
CunninghamM.ChoJ. H.LeungA.SavvidisG.AhnS.MoonM.et al. (2014). hPSC-derived maturing GABAergic interneurons ameliorate seizures and abnormal behavior in epileptic mice. Cell Stem Cell15, 559–573. 10.1016/j.stem.2014.10.006
11
DaCostaJ. C.PortuguezM. W.MarinowicD. R.SchillingL. P.TorresC. M.DaCostaD. I.et al. (2018). Safety and seizure control in patients with mesial temporal lobe epilepsy treated with regional superselective intra-arterial injection of autologous bone marrow mononuclear cells. J. Tissue Eng. Regen. Med. 12, e648–e656. 10.1002/term.2334
12
de Gois da SilvaM. L.da Silva OliveiraG. L.de Oliveira BezerraD.da Rocha NetoH. J.FeitosaM. L. T.Argolo NetoN. M.et al. (2018). Neurochemical properties of neurospheres infusion in experimental-induced seizures. Tissue Cell54, 47–54. 10.1016/j.tice.2018.08.002
13
DeverD. P.ScharenbergS. G.CamarenaJ.KildebeckE. J.ClarkJ. T.MartinR. M.et al. (2019). CRISPR/Cas9 genome engineering in engraftable human brain-derived neural stem cells. iScience15, 524–535. 10.1016/j.isci.2019.04.036
14
DuX.ParentJ. M. (2015). Using patient-derived induced pluripotent stem cells to model and treat epilepsies. Curr. Neurol. Neurosci. Rep.15, 71. 10.1007/s11910-015-0588-3
15
EL BarkyA. R.Mohamed AliE. M.MohamedT. M. (2017). Stem cells, classifications and their clinical applications. Am. J. Pharmacol. Therapeut.1, 1–7. Available online at: https://www.scireslit.com/Pharmacology/AJPT-ID11.php
16
ElittM. S.BarbarL.TesarP. J. (2018). Drug screening for human genetic diseases using iPSC models. Hum. Mol. Genet.27, R89–R98. 10.1093/hmg/ddy186
17
EngelJ.Jr. (2011). The etiologic classification of epilepsy. Epilepsia52, 1195–1197; discussion: 1205. 10.1111/j.1528-1167.2011.03065.x
18
FortierL. A.. (2005). Stem cells: classifications, controversies, and clinical applications. Vet. Surg.34, 415–423. 10.1111/j.1532-950X.2005.00063.x
19
FukumuraS.SasakiM.Kataoka-SasakiY.OkaS.NakazakiM.NagahamaH.et al. (2018). Intravenous infusion of mesenchymal stem cells reduces epileptogenesis in a rat model of status epilepticus. Epilepsy Res.141, 56–63. 10.1016/j.eplepsyres.2018.02.008
20
GalanopoulouA. S.BuckmasterP. S.StaleyK. J.MosheS. L.PeruccaE.EngelJ.Jr.et al. (2012). Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia53, 571–582. 10.1111/j.1528-1167.2011.03391.x
21
HammadM.SchmidtS. L.ZhangX.BrayR.FrohlichF.GhashghaeiH. T. (2015). Transplantation of GABAergic interneurons into the neonatal primary visual cortex reduces absence seizures in stargazer mice. Cereb. Cortex25, 2970–2979. 10.1093/cercor/bhu094
22
HammadiA. A.. (2019). Autologous bone marrow derived mononuclear cells for the treatment of drug resistant epilepsy. J. Stem Cell Res. Ther.5, 23–25. 10.15406/jsrt.2019.05.00129
23
HandreckA.Backofen-WehrhahnB.BroerS.LoscherW.GernertM. (2014). Anticonvulsant effects by bilateral and unilateral transplantation of GABA-producing cells into the subthalamic nucleus in an acute seizure model. Cell Transplant.23, 111–132. 10.3727/096368912X658944
24
HattiangadyB.KurubaR.ShuaiB.GrierR.ShettyA. K. (2020). Hippocampal neural stem cell grafting after status epilepticus alleviates chronic epilepsy and abnormal plasticity, and maintains better memory and mood function. Aging Dis.11, 1374–1394. 10.14336/AD.2020.1020
25
HattiangadyB.ShettyA. K. (2011). Neural stem cell grafting in an animal model of chronic temporal lobe epilepsy. Curr. Protoc. Stem Cell Biol. Chapter 2, Unit: 2D7. 10.1002/9780470151808.sc02d07s18
26
HattiangadyB.ShettyA. K. (2012). Neural stem cell grafting counteracts hippocampal injury-mediated impairments in mood, memory, and neurogenesis. Stem Cells Transl. Med.1, 696–708. 10.5966/sctm.2012-0050
27
HlebokazovF.DakukinaT.IhnatsenkoS.KosmachevaS.PotapnevM.ShakhbazauA.et al. (2017). Treatment of refractory epilepsy patients with autologous mesenchymal stem cells reduces seizure frequency: an open label study. Adv. Med. Sci.62, 273–279. 10.1016/j.advms.2016.12.004
28
HlebokazovF.DakukinaT.PotapnevM.KosmachevaS.MorozL.MisiukN.et al. (2021). Clinical benefits of single vs repeated courses of mesenchymal stem cell therapy in epilepsy patients. Clin. Neurol. Neurosurg.207, 106736. 10.1016/j.clineuro.2021.106736
29
HockemeyerD.JaenischR. (2016). Induced pluripotent stem cells meet genome editing. Cell Stem Cell18, 573–586. 10.1016/j.stem.2016.04.013
30
HuntR. F.GirskisK. M.RubensteinJ. L.Alvarez-BuyllaA.BarabanS. C. (2013). GABA progenitors grafted into the adult epileptic brain control seizures and abnormal behavior. Nat. Neurosci.16, 692–697. 10.1038/nn.3392
31
JiaoJ.YangY.ShiY.ChenJ.GaoR.FanY.et al. (2013). Modeling Dravet syndrome using induced pluripotent stem cells (iPSCs) and directly converted neurons. Hum. Mol. Genet.22, 4241–4252. 10.1093/hmg/ddt275
32
KaufmannM.SchuffenhauerA.FruhI.KleinJ.ThiemeyerA.RigoP.et al. (2015). High-throughput screening using iPSC-derived neuronal progenitors to identify compounds counteracting epigenetic gene silencing in fragile X syndrome. J. Biomol. Screen20, 1101–1111. 10.1177/1087057115588287
33
KimH. S.JeonI.NohJ. E.LeeH.HongK. S.LeeN.et al. (2020). Intracerebral transplantation of BDNF-overexpressing human neural stem cells (HB1.F3.BDNF) promotes migration, differentiation and functional recovery in a rodent model of Huntington's disease. Exp. Neurobiol.29, 130–137. 10.5607/en20011
34
KimH. W.QuanZ.KimY. B.CheongE.KimH. D.ChoM.et al. (2018). Differential effects on sodium current impairments by distinct SCN1A mutations in GABAergic neurons derived from Dravet syndrome patients. Brain Dev.40, 287–298. 10.1016/j.braindev.2017.12.002
35
KodaliM.CastroO. W.KimD. K.ThomasA.ShuaiB.AttaluriS.et al. (2019). Intranasally administered human MSC-derived extracellular vesicles pervasively incorporate into neurons and microglia in both intact and status epilepticus injured forebrain. Int. J. Mol. Sci.21:181. 10.3390/ijms21010181
36
KoliosG.MoodleyY. (2013). Introduction to stem cells and regenerative medicine. Respiration85, 3–10. 10.1159/000345615
37
KwanP.BrodieM. J. (2000). Early identification of refractory epilepsy. N. Engl. J. Med.342, 314–319. 10.1056/NEJM200002033420503
38
KwanP.BrodieM. J. (2004). Drug treatment of epilepsy: when does it fail and how to optimize its use?CNS Spectr.9, 110–119. 10.1017/s1092852900008476
39
LaiC. P.TannousB. A.BreakefieldX. O. (2014). Noninvasive in vivo monitoring of extracellular vesicles. Methods Mol. Biol.1098, 249–258. 10.1007/978-1-62703-718-1_19
40
LentiniC.d'OrangeM.MarichalN.TrottmannM. M.VignolesR.FoucaultL.et al. (2021). Reprogramming reactive glia into interneurons reduces chronic seizure activity in a mouse model of mesial temporal lobe epilepsy. Cell Stem Cell28, 2104.e10–2121.e10. 10.1016/j.stem.2021.09.002
41
LiT.SteinbeckJ. A.LusardiT.KochP.LanJ. Q.WilzA.et al. (2007). Suppression of kindling epileptogenesis by adenosine releasing stem cell-derived brain implants. Brain130(Pt 5), 1276–1288. 10.1093/brain/awm057
42
LinaresG. R.LengY.MaricD.ChuangD. M. (2020). Overexpression of fibroblast growth factor-21 (FGF-21) protects mesenchymal stem cells against caspase-dependent apoptosis induced by oxidative stress and inflammation. Cell Biol. Int.44, 2163–2169. 10.1002/cbin.11409
43
LoscherW.. (2017). Animal models of seizures and epilepsy: past, present, and future role for the discovery of antiseizure drugs. Neurochem. Res.42, 1873–1888. 10.1007/s11064-017-2222-z
44
LoscherW.KlitgaardH.TwymanR. E.SchmidtD. (2013). New avenues for anti-epileptic drug discovery and development. Nat. Rev. Drug Discov.12, 757–776. 10.1038/nrd4126
45
LuoM. L.PanL.WangL.WangH. Y.LiS.LongZ. Y.et al. (2019). Transplantation of NSCs promotes the recovery of cognitive functions by regulating neurotransmitters in rats with traumatic brain injury. Neurochem. Res.44, 2765–2775. 10.1007/s11064-019-02897-z
46
LybrandZ. R.GoswamiS.HsiehJ. (2020). Stem cells: a path towards improved epilepsy therapies. Neuropharmacology168, 107781. 10.1016/j.neuropharm.2019.107781
47
MilczarekO.JarochaD.Starowicz-FilipA.KwiatkowskiS.BadyraB.MajkaM. (2018). Multiple autologous bone marrow-derived CD271(+) mesenchymal stem cell transplantation overcomes drug-resistant epilepsy in children. Stem Cells Transl. Med.7, 20–33. 10.1002/sctm.17-0041
48
MiltiadousP.KouroupiG.StamatakisA.KoutsoudakiP. N.MatsasR.StylianopoulouF. (2013). Subventricular zone-derived neural stem cell grafts protect against hippocampal degeneration and restore cognitive function in the mouse following intrahippocampal kainic acid administration. Stem Cells Transl. Med.2, 185–198. 10.5966/sctm.2012-0074
49
NoakesZ.KeefeF.TamburiniC.KellyC. M.Cruz SantosM.DunnettS. B.et al. (2019). Human pluripotent stem cell-derived striatal interneurons: differentiation and maturation in vitro and in the rat brain. Stem Cell Rep.12, 191–200. 10.1016/j.stemcr.2018.12.014
50
NoebelsJ. L.AvoliM.RogawskiM. A. (2012). Jasper's Basic Mechanisms of the Epilepsies, 4th Edn. Bethesda, MD: National Center for Biotechnology Information.
51
PapazianI.KyrargyriV.EvangelidouM.Voulgari-KokotaA.ProbertL. (2018). Mesenchymal stem cell protection of neurons against glutamate excitotoxicity involves reduction of NMDA-triggered calcium responses and surface GluR1, and is partly mediated by TNF. Int. J. Mol. Sci.19:651. 10.3390/ijms19030651
52
ParentJ. M.YuT. W.LeibowitzR. T.GeschwindD. H.SloviterR. S.LowensteinD. H. (1997). Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J. Neurosci.17, 3727–3738.
53
Ramos-FresnedoA.Perez-VegaC.DomingoR. A.LeeS. J.PerkersonR. B.ZubairA. C.et al. (2022). Mesenchymal stem cell therapy for focal epilepsy: a systematic review of preclinical models and clinical studies. Epilepsia. 10.1111/epi.17266. [Epub ahead of print].
54
RoperS. N.SteindlerD. A. (2013). Stem cells as a potential therapy for epilepsy. Exp. Neurol.244, 59–66. 10.1016/j.expneurol.2012.01.004
55
RyuJ. K.ChoT.WangY. T.McLarnonJ. G. (2009). Neural progenitor cells attenuate inflammatory reactivity and neuronal loss in an animal model of inflamed AD brain. J. Neuroinflamm.6, 39. 10.1186/1742-2094-6-39
56
SadanandanN.SaftM.Gonzales-PortilloB.BorlonganC. V. (2021). Multipronged attack of stem cell therapy in treating the neurological and neuropsychiatric symptoms of epilepsy. Front. Pharmacol.12, 596287. 10.3389/fphar.2021.596287
57
SchefferI. E.BerkovicS.CapovillaG.ConnollyM. B.FrenchJ.GuilhotoL.et al. (2017). ILAE classification of the epilepsies: position paper of the ILAE commission for classification and terminology. Epilepsia. 58, 512–521. 10.1111/epi.13709
58
ShettyA. K.UpadhyaD. (2016). GABA-ergic cell therapy for epilepsy: advances, limitations and challenges. Neurosci. Biobehav. Rev.62, 35–47. 10.1016/j.neubiorev.2015.12.014
59
ShorvonS. D.. (2009a). Drug treatment of epilepsy in the century of the ILAE: the first 50 years, 1909-1958. Epilepsia50(Suppl 3), 69–92. 10.1111/j.1528-1167.2009.02041.x
60
ShorvonS. D.. (2009b). Drug treatment of epilepsy in the century of the ILAE: the second 50 years, 1959-2009. Epilepsia50(Suppl 3), 93–130. 10.1111/j.1528-1167.2009.02042.x
61
SunY.PascaS. P.PortmannT.GooldC.WorringerK. A.GuanW.et al. (2016). A deleterious Nav1.1 mutation selectively impairs telencephalic inhibitory neurons derived from Dravet Syndrome patients. eLife5, 13073. 10.7554/eLife.13073
62
SzczepanikE.MierzewskaH.Antczak-MarachD.Figiel-DabrowskaA.TerczynskaI.TryfonJ.et al. (2020). Intrathecal infusion of autologous adipose-derived regenerative cells in autoimmune refractory epilepsy: evaluation of safety and efficacy. Stem Cells Int.2020, 7104243. 10.1155/2020/7104243
63
TropelP.PlatetN.PlatelJ. C.NoelD.AlbrieuxM.BenabidA. L.et al. (2006). Functional neuronal differentiation of bone marrow-derived mesenchymal stem cells. Stem Cells24, 2868–2876. 10.1634/stemcells.2005-0636
64
UchidaN.ChenK.DohseM.HansenK. D.DeanJ.BuserJ. R.et al. (2012). Human neural stem cells induce functional myelination in mice with severe dysmyelination. Sci. Transl. Med.4, 155ra136. 10.1126/scitranslmed.3004371
65
UpadhyaD.HattiangadyB.CastroO. W.ShuaiB.KodaliM.AttaluriS.et al. (2019). Human induced pluripotent stem cell-derived MGE cell grafting after status epilepticus attenuates chronic epilepsy and comorbidities via synaptic integration. Proc. Natl. Acad. Sci. U.S.A.116, 287–296. 10.1073/pnas.1814185115
66
WaldauB.HattiangadyB.KurubaR.ShettyA. K. (2010). Medial ganglionic eminence-derived neural stem cell grafts ease spontaneous seizures and restore GDNF expression in a rat model of chronic temporal lobe epilepsy. Stem Cells28, 1153–1164. 10.1002/stem.446
67
WaloschkovaE.Gonzalez-RamosA.MikroulisA.KudlacekJ.AnderssonM.LedriM.et al. (2021). Human stem cell-derived GABAergic interneurons establish efferent synapses onto host neurons in rat epileptic hippocampus and inhibit spontaneous recurrent seizures. Int. J. Mol. Sci.22:13243. 10.3390/ijms222413243
68
WangL.ZhaoY.PanX.ZhangY.LinL.WuY.et al. (2021). Adipose-derived stem cell transplantation improves learning and memory via releasing neurotrophins in rat model of temporal lobe epilepsy. Brain Res.1750, 147121. 10.1016/j.brainres.2020.147121
69
WangS.WangB.PanN.FuL.WangC.SongG.et al. (2015). Differentiation of human induced pluripotent stem cells to mature functional Purkinje neurons. Sci. Rep.5, 9232. 10.1038/srep09232
70
WangY.ChenX.CaoW.ShiY. (2014). Plasticity of mesenchymal stem cells in immunomodulation: pathological and therapeutic implications. Nat. Immunol.15, 1009–1016. 10.1038/ni.3002
71
WatsonL. M.WongM. M. K.VowlesJ.CowleyS. A.BeckerE. B. E. (2018). A simplified method for generating Purkinje cells from human-induced pluripotent stem cells. Cerebellum17, 419–427. 10.1007/s12311-017-0913-2
72
WHO (2022). Epilepsy. WHO Fact Sheets. Available online at: https://www.who.int/en/news-room/fact-sheets/detail/epilepsy (accessed April 01, 2022).
73
WichterleH.Garcia-VerdugoJ. M.HerreraD. G.Alvarez-BuyllaA. (1999). Young neurons from medial ganglionic eminence disperse in adult and embryonic brain. Nat. Neurosci.2, 461–466. 10.1038/8131
74
XianP.HeiY.WangR.WangT.YangJ.LiJ.et al. (2019). Mesenchymal stem cell-derived exosomes as a nanotherapeutic agent for amelioration of inflammation-induced astrocyte alterations in mice. Theranostics9, 5956–5975. 10.7150/thno.33872
75
XuK.LiuF.XuW.LiuJ.ChenS.WuG. (2019). Transplanting GABAergic neurons differentiated from neural stem cells into hippocampus inhibits seizures and epileptiform discharges in pilocarpine-induced temporal lobe epilepsy model. World Neurosurg.128, e1–e11. 10.1016/j.wneu.2019.01.245
76
XuQ.CobosI.De La CruzE.RubensteinJ. L.AndersonS. A. (2004). Origins of cortical interneuron subtypes. J. Neurosci.24, 2612–2622. 10.1523/JNEUROSCI.5667-03.2004
77
YuJ.VodyanikM. A.Smuga-OttoK.Antosiewicz-BourgetJ.FraneJ. L.TianS.et al. (2007). Induced pluripotent stem cell lines derived from human somatic cells. Science318, 1917–1920. 10.1126/science.1151526
Summary
Keywords
stem cells, seizure, epilepsy, disease-modifying, genetic engineering, graft, disease models
Citation
Chang B-L and Chang K-H (2022) Stem Cell Therapy in Treating Epilepsy. Front. Neurosci. 16:934507. doi: 10.3389/fnins.2022.934507
Received
02 May 2022
Accepted
30 May 2022
Published
27 June 2022
Volume
16 - 2022
Edited by
Yu-Chen Hu, National Tsing Hua University, Taiwan
Reviewed by
Stephanie Schorge, University College London, United Kingdom
Updates
Copyright
© 2022 Chang and Chang.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Bao-Luen Chang baoluen@gmail.com
This article was submitted to Neurodegeneration, a section of the journal Frontiers in Neuroscience
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.