Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes
Abstract
:1. Introduction
2. MSC-Derived Exosomes as a Therapeutic Tool
3. Clinical Outcomes following MSC-Derived Exosome Treatment in Neurodegenerative Animal Models
4. Mechanism of Action
5. Limitations of Current Knowledge
6. Toward MSC-Derived Exosome-Based Therapies
7. MSC-Derived Exosomes in Clinical Trials
8. Summary
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Disease/Disorder | Reference | Animal Model | Cell Source | Dose | Route of Administration | Biological/Medical Improvement | Suggested Mechanism of Action |
---|---|---|---|---|---|---|---|
Alzheimer’s | [52] | Ovariectomized albino-rat | Rat BM | 100 μg | Intravenous (IV) | Improved in destructive structural changes in the taste buds and their innervations | Improved synaptophysin-immunoreactivity |
Alzheimer’s | [45] | APP/PS1 mouse | Mouse BM | 22.4 µg | Intracerebral | Reduced amount of dystrophic neurites in both the cortex and hippocampus | Aβ plaque reduction |
Alzheimer’s | [49] | Streptozotocin-induced mouse | Mouse BM | 0.5 μg/day for 5 days | Intraventricular | Recovered cognition impairment | Not mentioned |
Alzheimer’s | [46] | APP/PS1 mouse | Mouse BM | 100 μg | Intracerebroventricular | Improved cognitive behavior, rescued impairment of CA1 synaptic transmission, and long-term potentiation | Suppression of Aβ induced iNOS expression |
MS | [28] | EAE rat | Rat BM | 100/400 μg | IV | Decreased neural behavioral scores | Reduced demyelination and neuroinflammation |
Stroke | [32] | Subcortical infarction rat | Rat adipose | 50/100/200 μg | IV | Improved functional outcomes associated with decreased cell death | Restored fiber tract connectivity, increased oligodendrocyte markers, and re-myelination |
Stroke | [33] | MCAo rat | Rat BM | 120.68 μg | IV | Reduced neurological severity score; improved spatial learning and memory ability | Inhibited the expression of CysLT2R and NMLTC4 treated microglia; modulated the balance between M1 and M2 microglia; decreased pro-inflammatory cytokines secretion; increased anti-inflammatory and neurotrophic factors production |
Stroke | [53] | Cortical injured monkey | Monkey BM | 4 × 1011 particles/kg | IV | Enhanced recovery of fine motor function | Not mentioned |
Stroke | [40] | MCAo rat | Adipose (cell source not mentioned) | 3 treatments of 2.0 × 106 particles | IV | Reduced infarct volume; suppressed apoptosis | Improved BBB condition; suppressed inflammation; reduced abnormal high level of miR-21-3p |
Stroke | [54] | Intracerebral hemorrhage injection rat | Rat BM | 100 µg | IV | Improved spatial learning, motor function, and sensory memory | Promoting endogenous angiogenesis and neurogenesis; increased white matter remodeling |
Stroke | [70] | tMCAo rat | Rat BM | 30 µg | IV | Improved Neurological function | Promoted neurogenesis and angiogenesis via miR-184 and miR-210, respectively |
Stroke | [34] | Intracerebral hemorrhage rat | Rat adipose | 100 µg | IV | Improved functional recovery; reduced infarct size | Increased fiber tract and axonal sprouting; enhanced oligodendrocyte formation and remyelination |
Stroke | [47] | Transient global cerebral ischemia mouse | Mouse BM | 200 µg | Intracerebroventricular | Restored impaired basal synaptic transmission and synaptic plasticity, and improved spatial learning and memory | Inhibited pathogenic expression of COX-2 in the hippocampus |
Stroke | [35] | Subcortical infarct rat | Rat adipose | 100 µg | IV | Improved functional recovery | Increased axonal sprouting and growth, oligodendrocyte formation, tract connectivity and remyelination |
Stroke | [36] | MCAo rat | Mini-pig adipose | 100 µg | IV | Reduced brain infarct zone; improved neurological function | Suppressed inflammation; reduced ROS and oxidative stress generation; promoted angiogenesis |
Stroke | [69] | MCAo rat | Rat BM | 100 µg | IV | Improved neurologic outcome | Enhanced neurite remodeling, neurogenesis, and angiogenesis |
Neuroinflammation | [44] | LPS-induced rat | Rat BM | 200 µg | IV | Enhanced neuronal survival | Reduced oxidative stress; reduced inflammatory response |
TBI | [41] | Controlled cortical impact (CCI) mouse | Rat BM | 30 µg | Retro-orbital | Improved functional recovery; reduced cortical lesion volume; attenuated cellular apoptosis | Inhibited early neuroinflammation through modulation of microglia/macrophages polarization |
TBI | [59] | CCI rat | Rat BM | 100 µg | IV | Cognitive and sensorimotor improvement. | Promotion of endogenous angiogenesis and neurogenesis; and inflammation reduction. |
SCI | [38] | Spinal cord hemisection rat | Rat BM | 100 µg | IV | Improved functional recovery and attenuated lesion size and apoptosis | Targeted inhibition of the FasL gene by miR-21-5p |
SCI | [42] | Rat contusive SCI | Rat BM | 1 × 106 cells equivalents | IV | Reduced neuronal cell apoptosis, enhanced neuronal survival and regeneration, and improved motor function | Suppression of pericytes migration; and improved blood-spinal cord barrier integrity via NF-κB p65 signaling |
SCI | [39] | Rat contusive SCI | Rat BM | 100 µg | IV | Suppressed glial scar formation; attenuated lesion size; promoted axonal regeneration; and improved functional behavioral recovery | Promoted blood vessel formation; reduced neuronal cells apoptosis; suppressed inflammation; and suppressed activation of A1 neurotoxic reactive astrocytes |
SCI | [30] | Spinal cord hemisection injured rat | Rat BM | 100 µg | IV | Reduced disease severity | Inhibited complement mRNA synthesis and release; inhibited activation of NF-κB signaling by binding to microglia cells. |
SCI | [48] | Rat contusive SCI | Rat BM | 1 × 106 cells equivalents | IV | Improved locomotor function; and the neuroprotective effect on residual neurons, synapses, and myelin sheath. | Reduced A1 astrocyte proportion by inhibiting NFκB activation; reductions in proinflammatory cytokine levels |
SCI | [31] | Rat contusive SCI | Rat BM | 100 µg | IV | Attenuated lesion size and improved functional recovery | Attenuated cellular apoptosis and inflammation; promoted angiogenesis |
Disease/Disorder | Reference | Animal Model | Cell Source | Dose | Root of Administration | Biological/Medical Improvement | Suggested Mechanism of Action |
---|---|---|---|---|---|---|---|
Alzheimer’s | [50] | Aβ-inoculated mouse | Human, purchased from ATCC | 10 µg | Intrahippocampal | Enhance neurogenesis and restore cognitive function | Not mentioned |
Alzheimer’s | [51] | APP/PS1 mouse | Human umbilical cord | 30 µg | IV | Repair cognitive disfunctions | Help to clear Aβ deposition; and modulate the activation of microglia in the brain |
MS | [29] | EAE mouse | Human BM | 150 μg | IV | Reduced disease severity | Reduced demyelination; decreased neuroinflammation; and upregulated the number of regulatory T cells |
Stroke | [55] | MCAo rat | Human umbilical cord blood | 150 µg | IV | Attenuated infarct size; exacerbated the somatosensory and motor dysfunction | Not mentioned |
Stroke | [37] | MCAo mouse | Human BM | Released by 2 × 106 MSCs | IV | Improved neurological impairment and long-term neuroprotection | Promoted neurogenesis and angiogenesis; prevented post-ischemic immunosuppression |
Perinatal brain injury | [56] | A combination of a hypoxic-ischemic and an inflammatory insult in rat | Human Wharton’s jelly | 50 mg/kg | Intranasal (IN) | Improved long-term neurodevelopmental outcome | Prevented gray and white matter alterations |
Perinatal brain injury | [43] | Rice-Vannucci mouse | Human BM | 1.25 × 109 particles/dose | IN | Improved short-term behavioral outcomes; reduced tissue volume loss and cell death | Reduced microglial activation |
Perinatal brain injury | [57] | LPS-induced rat | Human BM | 1 × 108 cell equivalents/kg bodyweight | Intraperitoneal (IP) | Improved long-lasting cognitive functions | Ameliorated inflammation-induced neuronal cellular degeneration; reduced microgliosis; prevented reactive astrogliosis; and restored short-term myelination deficits and long-term microstructural abnormalities of the white matter |
Perinatal brain injury | [58] | Transient umbilical cord occlusion in preterm ovine fetus | Human BM | Two boluses of 2.0 × 107 cell equivalents | IV | Reduced total number and duration of seizures; and preserved baroreceptor reflex sensitivity | Hypomyelination prevention |
TBI | [61] | A combination of CCI and hemorrhagic shock swine | Human BM | 1 × 1013 particles | IV | Reduced the severity of neurological injury and improved neurocognitive recovery | Not mentioned |
TBI | [60] | CCI mouse | Human BM | 30 µg | IV | Rescued pattern separation and spatial learning impairments | Immunomodulation |
SCI | [62] | Mouse contusive SCI | Human umbilical cord | 20/200 µg | IV | Promoted locomotor functional recovery | Attenuated inflammation of the injury region |
SCI | [63] | Spinal cord contusion rat | Human BM | 1 × 109 particles | IV | Improved locomotor recovery score; improved mechanical sensitivity | Diminished inflammatory response |
SE | [64] | Pilocarpine mouse | Human umbilical cord | 30 µg | Intraventricular | Ameliorated learning and memory impairments | Reduced inflammatory responses associated with hippocampal astrocyte activation via Nrf2-NF-κB signaling pathway |
SE | [65] | Pilocarpine mouse | Human BM | 30 µg | IN | Long-term preservation of normal hippocampal neurogenesis and cognitive and memory function | Diminished loss of glutamatergic and GABAergic neurons; and reduced inflammation in the hippocampus |
Disease/Disorder | Reference | Animal Model | Cell Source | The Addition | Dose | Route of Administration | Biological/Medical Improvement | Suggested Mechanism of Action |
---|---|---|---|---|---|---|---|---|
Alzheimer’s | [92] | APP/PS1 mouse | Mouse BM | Rabies viral glycoprotein (RVG) | 4 boluses of 5 × 1011 particles | IV | Improved learning and memory function | Decreased plaque deposition and Aβ levels; reduced astrocytes activation; reduced pro-inflammatory mediators and raised anti-inflammatory factors |
MS | [87] | EAE mouse | Mouse BM | LJM-3064 aptamer | 200 μg | IV | Reduced disease severity | Suppressed of inflammatory response; lowered demyelination lesion region |
Stroke | [77] | MCAo rat | Rat BM | miR-29b-3p | 100 μg/kg/day for 3 days | Intracerebroventricular | Reduced infarct volume | Suppressed neuronal apoptosis and promoted angiogenesis through the downregulation of PTEN and activation of Akt signaling pathway |
Stroke | [93] | MCAo rat | Human BM | Iron oxide nanoparticles (IONP) | 200 μg | IV | Decreased infarction volume and improved motor function | Promoted the anti-inflammatory response, angiogenesis, and anti-apoptosis |
Stroke | [78] | MCAo rat | Rat adipose | miR-126 | Not mentioned | IV | Enhanced functional recovery | Inhibited microglial activation and inflammatory response; promoted neurogenesis and vasculogenesis |
Stroke | [88] | Transient MCAo rat | Rat BM | Transferrin and enkephalin | One or two boluses of 5 × 104 | IV | Improved brain neuron density and neurological score | Decreased levels of LDH, p53, caspase-3, and NO |
Stroke | [82] | MCAo rat | Mouse BM | c(RGDyK) peptide and miR-210 | 100 µg | IV | Enhanced survival rate | Promoted angiogenesis; up-regulation of integrin β3 and CD34 expression |
Stroke | [90] | MCAo mice | Mouse BM | c(RGDyK) peptide and curcumin | 100 µg | IV | Reduced cellular apoptosis in the legion region | Suppressed inflammatory response |
Stroke | [15] | Intracerebral hemorrhage rat | Rat BM | miR-133b | 100 μg | IV | Reduced apoptotic and neurodegenerative neurons | Inhibited RhoA and activation of ERK1/2/CREB pathway |
Stroke | [89] | MCAo rat | Rat adipose | Pigment epithelium-derived factor (PEDF) | 100 μg/kg/day for 3 days | Lateral cerebral ventricle | Reduced infarct volume; suppressed neuronal apoptosis | Activated autophagy |
Stroke | [79] | Modified MCAo rat | Rat adipose | miR-30d-5p | 80 μg | IV | Decreased cerebral injury area of infarction | Suppressed autophagy and promoted M2 microglia/macrophage polarization |
Stroke | [81] | MCAo rat | Rat BM | miR-17-92 | 100 µg | IV | Improved neurological outcome | Increased neural remodeling including neurogenesis, oligodendrogenesis and neurite plasticity; inhibited PTEN, and subsequently increased the phosphorylation of PTEN downstream proteins, Akt, mTOR and GSK-3β |
TBI | [91] | Electric cortical contusion impactor rat | Rat BM | BDNF | 100 µg | IV | Inhibit apoptosis | Inhibited inflammation and promoted neuronal regeneration; increased miR-216a-5p |
TBI | [80] | Controlled cortex injury rat | Rat BM | miR-124 | 100 µg | IV | Improved neurological function recovery | Reduced production of pro-inflammatory cytokines; promoted M2 polarization of microglia; increased production of anti-inflammatory cytokines; enhanced neurogenesis in hippocampus |
SCI | [86] | Complete spinal cord transection rat | Human BM | Phosphatase and tensin homolog (PTEN) siRNA | 5 boluses of 1.62 × 108 particles | IN | Elicited functional recovery; improved structural and electrophysiological function | Enhanced axonal growth and neovascularization; reduced microgliosis and astrogliosis |
SCI | [84] | Spinal cord ischemia rat | Rat BM | miR-25 | 20 µg | Intrathecal | Improved MDI (motor deficit index); enhanced neuroprotection | Reduced pro-inflammatory cytokines; reduced oxidative stress markers |
SCI | [85] | Rat contusive SCI | Rat BM | miR-29b | 100 µg | IV | Increased BBB score | Decreased contractile nerve cell numbers and GFAP positive neurons |
SCI | [83] | Compression SCI rat | Rat BM | miR-133b | 100 μg | IV | Improved recovery of hindlimb locomotor function | Preserved neurons; promoted regeneration of axons; activated ERK1/2, STAT3, and CREB; inhibited RhoA expression |
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Guy, R.; Offen, D. Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes. Biomolecules 2020, 10, 1320. https://doi.org/10.3390/biom10091320
Guy R, Offen D. Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes. Biomolecules. 2020; 10(9):1320. https://doi.org/10.3390/biom10091320
Chicago/Turabian StyleGuy, Reut, and Daniel Offen. 2020. "Promising Opportunities for Treating Neurodegenerative Diseases with Mesenchymal Stem Cell-Derived Exosomes" Biomolecules 10, no. 9: 1320. https://doi.org/10.3390/biom10091320