Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Epilepsy and Their Interaction with Antiseizure Medications
Abstract
:1. Introduction
2. MSCs
2.1. Umbilical Cord-Derived Mesenchymal Stem Cells (UC-MSCs)
2.2. Bone Marrow Mesenchymal Stem Cells (BMSCs)
2.3. Adipose-Derived Stem Cells (ADSCs)
3. Mechanisms for MSCs Enhanced Neuroprotection
4. Possible Mechanisms of Anti-Seizure Effects of MSCs-Based Therapy
5. The Effect of ASMs on MSCs
5.1. The Effect of Valproic Acid (VPA) on MSCs
Drugs | The Source of MSCs | Genes and Signaling Pathways Involved | Ref. |
---|---|---|---|
Valproic acid | Cryopreserved rat MSCs | Increased cell migration ability | [110] |
Human umbilical cord-derived MSCs | Enhancement of cell migration and potentiating anti-inflammatory and immunity pathways | [111] | |
Human bone marrow-derived MSCs | Increased function of stem cells by increasing the expression of CXCR7 | [112] | |
Cord blood mesenchymal stromal cells | Increased cell migration according to increased activity of SDF1/CXCR4 and SDF-1/CXCR7 signaling pathways | [113] | |
Human bone marrow-mesenchymal stromal cells | Increased expression of KRIT1 and prevention of the accumulation of intracellular oxidants and reduction of oxidative stress | [114] | |
Human umbilical cord-derived MSCs | Increased expression of mesenchymal and endodermal genes related to hepatic tissue/strengthening of CXCR4 signaling | [115] | |
Human MSCs derived from adipose tissue | Increased MSCs migration ability by activating the CXCR4 signaling pathway | [116] | |
Human bone marrow-derived mesenchymal stromal cells | Activation of CXCR4 signaling pathway and increased MSCs immortality | [117] | |
Human bone marrow-derived MSCs | Increased expression of liver markers such as ALB, AFP, CK-18, TAT and increasing the differentiation of MSCs into liver cells | [118] | |
Human umbilical cord-derived MSCs | Regulation of the expression of a group of miRNAs and hepatic differentiation | [119] | |
Adipose tissue and bone marrow-derived MSCs | Increased expression of osteogenic genes such as RUNX, BMP2, p21WAF1, osterix, and osteopontin | [9] | |
Tonsil-derived MSCs | Increased bone differentiation with CCN1 protein expression | [120] | |
MSCs derived from pancreatic islets | Increased expression of genes related to beta cell neogenesis, such as NKX6.1/increase in the number of insulin-positive cells | [121] | |
Mouse lip derived-MSCs | Increased expression of cardiac structural genes such as Cx43, βMHC, cTnI, and MLC2v and cardiac primary transcription genes such as NKX2.5, HAND2, HAND1, and GATA4 | [122] | |
Human Wharton’s jelly MSCs | Increased expression of neuronal markers such as Nestin, Neuro-D1 | [123] | |
Human bone marrow-derived mesenchymal stromal cells | Increased expression of neuronal markers such as GFAP, Musashi, CD133, Nestin-1, MAP-2, and KCNH2/5 | [124] | |
Human bone marrow-derived MSCs | Increased expression of markers of mature neurons such as Th, VAChT and Htr2a/decreased expression of oligodendrocyte and primary neurons precursors | [125] | |
Mammary fat tissue and cord blood MSCs | Cell cycle inhibition in G2/M phase/enhancement of p21CIP1/WAF1 signaling pathway activity and cell cycle inhibition | [126] | |
Mouse MSCs derived from bone marrow | Regulation of the expression of genes involved in energy metabolism such as PGC-1α, Cox6b2, and Atp12a and genes involved in antioxidant defense such as Serpinb1b, Gpx6, and Mt2/increased expression of genes involved in cell stress pathway such as Hsp27, Hox, and Hsp A1l, and anti-apoptotic pathways such as Erc1, Naip1, and Faim2/elevated expression of growth and trophic factors such as FGF-15, FGF-21, NDNF, GDF-1, BMP-3, and NTF3 | [127] | |
Human bone marrow-derived MSCs | Apoptosis induction and antiproliferative effects in T cells | [128] | |
Cryopreserved rat MSC | Enhancement of CXCR4 signaling/increased expression of mesenchymal markers such as fibronectin and CD54 | [129] | |
Human bone marrow-derived MSCs | Increased expression of tumor suppressor genes such as Cx43 and Cx26 and induction of apoptosis | [130] | |
Phenytoin | Dental pulp-derived-MSCs Mouse lip derived-MSCs | Increased expression of osteoblast-related markers such as osteopontin, RUNX2, and ALP Increased expression of miR-196a-5p and defective cell proliferation | [131,132] |
Levetiracetam | Adipose and bone marrow derived MSCs Human Wharton’s jelly MSCs | Modulation of the release of inhibitory and excitatory neurotransmitters/regulation of the release of inflammatory factors such as bFGF, TNF-a, IL-6, and BDNF Regulation of the expression of antioxidant genes such as Cu/ZnSOD, signaling proteins such as PEBP1/regulation of the expression of genes related to apoptosis, survival and cell death such as BDNF/GDNF | [133,134] |
Pregabalin | Bone marrow-derived MSCs | Decreased Notch1/p38-MAPK signaling pathway activity/ Reduction of the level of inflammatory markers such as TNF-α, NF-κB, p65, and IL-6/ Increased level of antioxidants | [135] |
Gabapentin | Ovine-derived mesenchymal stem cells | Increased speed of mesenchymal cell division | [136] |
Phenobarbital | TERA2.cl.SP12 stem cells | Induction of necrosis in neurons and reducing their differentiation | [137] |
Carbamazepine | TERA2.cl.SP12 stem cells | Impairment of cell proliferation and reduced cell viability | [137] |
Lamotrigine | TERA2.cl.SP12 stem cells | Induction of necrosis and reduction of cell viability | [137] |
5.2. The Effect of Phenytoin on MSCs
5.3. The Effect of Levetiracetam (LEV) on MSCs
5.4. The Effect of Pregabalin on MSCs
5.5. The Effect of Gabapentin on MSCs
6. Human Stem Cell Lines and Risk of Developmental Neurotoxicity with ASMs
7. Limitations of MSCs
8. Ethical Issues
9. Potential Risks and Adverse Effects
10. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Stem Cells | 1-Allogenic adult stem cells, derived from another person’s specialized tissue; have ethical concern 2-Autologous adult stem cells, derived from the individual’s own specialized tissue; without ethical concern | Embryonic stem cells | Origin | Characteristic | Types | Ethical Issues | Ref |
Derived from an embryo in the first four blastomeric cleavage phases | Totipotent | - |
| [27] | |||
Derived from an embryo after the fourth blastomeric cleavage phase | Pluripotent | Embryonic stem cell | [28] | ||||
Adult stem cells | Mesenchymal stem cells (MSCs) | Multipotent | Umbilical cord-derived mesenchymal stem cells, bone marrow, and adipose-derived mesenchymal stem cells | Since the use of these cells does not require the destruction of the embryo, it brings fewer ethical problems. However, as allogenic stem cells contain donor DNA, this may be associated with safety, legal and ethical challenges associated with the privacy of individuals. Autologous stem cells do not pose a particular ethical problem and do not interfere with the recipient’s immune system [29,30] | [31,32,33] | ||
Induced pluripotent stem cells | Pluripotent | Fibroblasts, dental pulp, deciduous teeth, renal epithelial cells, and urine | [34,35,36] | ||||
Neural stem cells. Derived out of the periventricular sub-ependymallayer and sub-granular zone of the dentate gyrus | Multipotent | Glia (oligodendrocyte precursor cells) and neurons | [37,38] | ||||
Hematopoietic stem cells | Multipotent | Lymphoid progenitor cells, hemangioblasts, peripheral blood stem cells, myeloid progenitor cells | [39,40,41,42] | ||||
Myoblasts | Multipotent | Cardiac, skeletal, smooth muscle cells | [43,44,45] |
Model | Type of Stem Cell | Injection Method | Volume Concentration | Measured Parameters | Findings | Ref |
---|---|---|---|---|---|---|
Pilocarpine induced SE rats | hUC-MSCs | Bilateral intra hippocampus | 105 cells | Hippocampal morphology/inhibitory transmission/epileptic properties | Recovery of hippocampal and GABAergic neurons/Reduced duration and incidence of epilepsy/Maintenance of neuronal circuits’ integrity/Attenuation of MFS and glutamate toxicity/Expression of various cytokines | [58] |
Pilocarpine-lithium induced SE rats | hUCBC | Tail vein | 1 × 106 cells/rat | Frequency and duration of SRS/hippocampal neuronal densities | Both frequency and duration of SRS were decreased/elevated neuronal densities in the hippocampus | [59] |
PTZ-induced epileptic rats | hUCB-MSCs | Tail vein | 106 MSCs/rat | Cognitive and motor function/seizure activity/oxidant and antioxidant measurements/GABA level determination | Decreased oxidative stress impairments and cognitive and motor dysfunction/enhanced GABAergic circuits | [60] |
Lithium- pilocarpine induced SE rats | hUCB-MSCs | Intra right hippocampus | 5 × 105/2 µL | Hippocampal volume/inflammatory changes/hippocampal glucose metabolism | Elevated hippocampal glucose metabolism/bilaterally migration of cell in hippocampi | [61] |
Pilocarpine induced SE mice | MSC-EVs | In vitro/In vivo; Intravenous | 50 μg MSC-EVs diluted in 150 μL sterile PBS | Anti-oxidative function/SE activity/neural function and morphology | Antioxidant activity of MSC-EVs by Nrf2 signaling/restore structural alterations and neuronal dysfunction/learning, memory and SE improvement | [62] |
Human model of drug-resistant epilepsy | Autologous BMSCs Neuro-induced MSCs | Intravenous | 2–5 × 106 cells/mL 2.7–8 × 106 cells/mL | Epileptic activity/cognitive function | Cognitive improvements/immunoregulatory effects | [63] |
Lithium- pilocarpine induced SE rat | Autologous BMSCs | Intravenous | 1.0 × 106 cells/mL | Seizure frequency/ cognitive function | Reduced neuronal cell death/Inhibition of aberrant MFS/Cognitive function improvement/Attenuation of epileptogenesis | [64] |
Kainic acid induced SE rat | BMSCs | Bilateral intraventral hippocampus | 20,000 cell in 1.5 μL PBS | Epileptic activity | MSC transplant did not change the duration and severity of seizure | [65] |
Kindling epilepsy rats | Autologous BMSCs | Unilateral intrahippocampal | 2 μL | Adenosine receptors expression | Bidirectional change in adenosine receptors/Maintenance of the balance of adenosine receptors | [66] |
Kindling epilepsy rats | ESCs | Lateral brain ventricles | - | Seizure activity | Prevention of seizure activity | [67] |
Kainic acid induced epileptic mouse | hMSCs | Infrahippocampal | 2.5 μL | Seizure activity | hMSCs worked as a vehicle to deliver adenosine/ Improvement of seizure activity | [68] |
Kainic acid induced epileptic rats | hMSCs | Left hippocampus | 5 μL | Brain injury/ hippocampal morphology/epileptic activity | Reduced seizure duration and hippocampal neural loss/Amelioration of seizures/Reduced apoptosis | [69] |
Pilocarpine induced epileptic rats | BMSCs | Intravenous | 500 mL | Histological and morphological analysis/ | Functional and structural improvements of hippocampus | [70] |
Lithium-induced SE rats | BMCs | Intravenous | 1 × 107 cells/mL | Epileptic activity/morphological change/LTP | Lower duration and frequency/ suppressed seizure/Decreased neural lose/Prevention of spontaneous seizures/Reduction of cell loss and hippocampal change/Improvement of LTP formation | [71] |
Pilocarpine induced epileptic rats | BMCs | Intravenous | 1 × 107 cells/mL in a volume of 100 μL | Seizure activity/ inflammatory and anti-inflammatory cytokines/ | Seizure duration and frequency reduction/Decreased pro-inflammatory cytokines/Elevation of anti-inflammatory cytokine | [72] |
Lithium chloride pilocarpine induced epileptic rats | BMSCs | Right lateral ventricle | 5 × 106 cells | GABAergic transmission/epileptic activity | Hes1 silencing caused BMSCs to differentiate into GABAergic neuron | [73] |
Pilocarpine induced epileptic rats | BMSCs | lateral ventricle | 5 × 106 cells | Epileptic activity/cell migration and differentiation | Rate of mortality reduction/SRS frequency and epileptic activity decreased/GABAergic neurons increased | [74] |
Pilocarpine induced SRS rats | BMMCs | Tail vein | 1 × 107 cells | Expression levels of GDNF, NGF, BDNF, TGF-β1, and VEGF, and their receptors | Upregulation of trophic and growth factors/Neuroprotective effects | [75] |
PTZ-induced epileptic seizures rats | BMSCs | Intravenous | 3 × 106 cells/rat | The level of excitatory and inhibitory neurotransmitters/oxidative and anti-oxidative factors/HPA axis hormones | Reduction in epileptic activity by balancing between inhibitory and excitatory neurotransmitters/ Anti-oxidant activity/Modulation of sex hormonal profile and inflammatory response | [76] |
Pilocarpine induced epileptic rats | BMSCs | Intravenous | 2 × 107 cells | Excitatory and inhibitory neurotransmitters concentration/oxidation and anti-oxidation activity/immunomodulatory factors | Reduction in oxidative functions and lipid peroxidation/Downregulation of inflammatory cytokines/Upregulation of anti-inflammatory cytokines and IGF-R signaling/Reduced excitation in hippocampus | [77] |
Pilocarpine induced epileptic rats | BMMCs | Intravenous | 1 × 107 cells | Cytokine production/epileptic activity | Reduced inflammatory cytokines/Increased anti-inflammatory cytokines | [78] |
Pilocarpine induced epileptic rats | BM-MSCs AD-MSCs | Tail vein | 100 µL | HSP-70, S100β, and caspase-8 levels/TLR-4/BBB integrity | Decline in the level of S100β, HSP-70, and caspase-8, and TLR-4 gene expression/Neuroprotection/Reduced neural loss | [79] |
Temporal lobe epilepsy patients | BMMC | Intra-arterial | 15 mL 1.52 × 108 to 10 × 108 cells | MRI/EEG/verbal and nonverbal memory | Better memory performance/Decreased epileptic spikes | [80] |
Lithium–pilocarpine induced-SE rats | BMMCs | Intravenous | 1×107 cells in 200 μL | SRS activity/cognitive function | Decline in frequency of seizures/Improved long-term spatial memory and learning | [81] |
Kainic acid induced epileptic rat | ADSC | Intra left hippocampus | 50,000 cells | Neuronal cell markers/learning and memory/neurotrophins/apoptotic and anti-apoptotic factors | Elevated anti-apoptotic and neuronal cell marker expression/Learning and memory improvement | [82] |
Pilocarpine induced epileptic mice | ADSC | Intraperitoneal | 40 mg/kg | BBB leakage/SRS/cognitive functions | Attenuation of seizure spikes/Reduced BBB leakage | [83] |
Convulsive seizure induction by maximum electroshock, mice model of seizure | MCAT | Intrahippocampal | 1 × 105 cells (50,000 per hemisphere) | Seizure duration and activity/mortality rate/inflammatory and anti-inflammatory markers | Anticonvulsant effects/Downregulation of inflammatory markers | [84] |
Model | Type of Stem Cell | Injection Method | Volume Concentration | Measured Parameters | Findings | Ref |
---|---|---|---|---|---|---|
DS patient- derived induced pluripotent stem cells | hUC-MSCs | In vitro | - | Oxidative stress markers/Ca 2+ levels/Inflammation | Increased anti-oxidative enzymes: GSH, SOD1/2, and GPX and reduced oxidative markers: MDA, Ca 2+ and ROS/Elevated anti-inflammatory factors: TGF-β and IL-10/6 and lowered interleukin-1 and TNF-α | [85] |
Drug-resistant epilepsy patients | Autologous BMSCs | Intravenous injection followed by intrathecal injection | 1.0–1.5 × 106 cells/kg/f 0.1 × 106 cells/kg, respectively | Epileptic activity/Seizure frequency/Depression and anxiety | Decreased seizure frequency and paroxysmal activity/Reduced depression and anxiety score | [8] |
Drug-resistant epilepsy patients | BMNCs | Intrathecal BMNCs: 0.5 × 109; intravenous: 0.38 × 109–1.72 × 109 BMMSCs: 18.5 × 106–40 × 106 | - | Cognitive function/ Epileptic seizure | Cognitive and neurological improvement | [86] |
Autoimmune refractory epilepsy patients | Autologous ADRCs | Intrathecal 3 times every 3 months | 4 mL | Cognitive function/Epileptic effects/Inflammatory and anti-inflammatory markers | Elevated level of anti-inflammatory cytokines/Reduced epileptic activity/Cognitive function improvement | [87] |
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Tesiye, M.R.; Gol, M.; Fadardi, M.R.; Kani, S.N.M.; Costa, A.-M.; Ghasemi-Kasman, M.; Biagini, G. Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Epilepsy and Their Interaction with Antiseizure Medications. Cells 2022, 11, 4129. https://doi.org/10.3390/cells11244129
Tesiye MR, Gol M, Fadardi MR, Kani SNM, Costa A-M, Ghasemi-Kasman M, Biagini G. Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Epilepsy and Their Interaction with Antiseizure Medications. Cells. 2022; 11(24):4129. https://doi.org/10.3390/cells11244129
Chicago/Turabian StyleTesiye, Maryam Rahimi, Mohammad Gol, Mohammad Rajabi Fadardi, Seyede Nasim Mousavi Kani, Anna-Maria Costa, Maryam Ghasemi-Kasman, and Giuseppe Biagini. 2022. "Therapeutic Potential of Mesenchymal Stem Cells in the Treatment of Epilepsy and Their Interaction with Antiseizure Medications" Cells 11, no. 24: 4129. https://doi.org/10.3390/cells11244129