Table 3.
Stem cell-derived exosomes for the treatment of diseases in neurosurgery and related specialties
| Target disease | Exosome | In vitro model & findings | In vivo model & findings | Refs. |
|---|---|---|---|---|
| Ischemic stroke | NSC-exo | SH-SY5Y cells; inhibited apoptosis and promoted proliferation both in normal and OGD conditions | rat MCAO model; reduced infarction area and neuron apoptosis, exosomal miR-150-3p enhanced neuroprotective effects by targeting CASP2 | 135 |
| EPC-exo | N/A | rat MCAO model; reduced infarct size, neurological defect score, and percentage of apoptotic cells, but increased CD31 and VEGF | 137 | |
| IFN-γ induced NSC-exo | NSCs; increased cell proliferation & survival, and reduced cell apoptosis | rat MCAO model; promoted behavioral and structural outcomes; inflammatory factor IFN-γ preconditioned exo were more potent | 138 | |
| BM-MSC-exo | OGD N2a cells, rat primary cortical neurons; neuroprotective against NLRP3 inflammasome-mediated pyroptosis | N/A | 139 | |
| iPSC-exo | rat primary cortical neurons; improved neuronal survival and neurite outgrowth via PTEN/Akt pathway | N/A | 140 | |
| NSC-exo, iCM-exo | primary mouse cortical astrocytes, neuronal cells; protected after OGD ischemia; NSC-exo > iCM-exo | mice; reduced infarct volume | 141 | |
| Zeb2/Axin2 enriched BM-MSC-exo | OGD rat neuron; increased neurite branching & elongation | rat MCAO model; improved post-stroke neurogenesis, neural plasticity, and spatial memory and nerve function, likely via SOX10, Wnt/β-catenin, and endothelin-3/EDNRB pathways | 142 | |
| miR-126-EPC-exo | N/A | diabetic mouse MCAO model; improved acute brain injury and functional recovery after stroke by promoting neurogenesis | 143 | |
| BM-MSC-exo | BV2 microglia; induced microglia deactivation and M2 polarization | rat MCAO model; reduced infarct size and improved neuronal function via transferring miR-23a-3p | 144 | |
| UC-MSC-exo | BV2 microglia; attenuated microglia-mediated inflammation after OGD | mice; reduced infarct volume, behavioral deficits, and ameliorated microglia activation; exosomal miR-146a-5p reduced neuroinflammation via IRAK1/TRAF6 pathway | 145 | |
| TSG101-oe-NSC-exo | N2A cells; attenuated LDH release and proinflammatory factors, | rat MCAO model; reduced infarction volume & inflammatory cytokines, inhibited DNA-damage pathway, and upregulated neurotrophic factors | 146 | |
| RGD NSC-exo | ReN & BV2 cells; showed intrinsic anti-inflammatory activity | mice; targeted ischemic brain regions and suppressed postischemia inflammatory response; exosomal miRs inhibited MAPK pathway | 147 | |
| BDNF-NSC-exo | H2O2-induced oxidative stress in NSCs; reduced apoptosis and increased neurogenic differentiation | rat MCAO model; inhibited the activation of microglia, promoted the differentiation of endogenous NSCs into neurons, and improved behavioral function | 149 | |
| miR-210-EPC-exo | H/R injured SH-SY5Y cells; protected from apoptosis & oxidative stress | N/A | 150 | |
| ACE2-enriched EPC-exo | H/R injured mouse brain microvascular endothelial cells; inhibited senescence | mouse MCAO model; exosomal miR-17-5p inhibited apoptosis, oxidative stress & brain dysfunction via PTEN/PI3K/Akt pathway | 152 | |
| NSC-exo + EPC-exo | H/R injured SH-SY5Y cells; protected from apoptosis & oxidative stress | rat MCAO model; reduced infarct volume & neurological deficits score via Nox2/ROS & BDNF/TrkB pathways | 153 | |
| Traumatic brain injury | MSC-exo | N/A | rats; improved spatial learning & sensorimotor function and neurovascular plasticity | 159 |
| BM-MSC-exo | N/A | rats; improved spatial learning, and 3D > 2D culture conditions; enhanced sensorimotor recovery; increased endothelial cells & neurons, and reduced neuroinflammation | 160 | |
| MSC-exo | N/A | primary motor cortex monkey model; animals returned to pre-operative grasp patterns & latency to retrieve food reward in the first 3–5 weeks of recovery | 161 | |
| MSC-exo | N/A | combined TBI & HS swine model; attenuated severity of neurologic injury and allowed for faster neurologic recovery | 162 | |
| adipose MSC-exo | primary rat microglia & neuron; suppressed microglia activation by inhibiting NF-κB & MAPK | rats; promoted functional recovery, suppressed neuroinflammation, reduced neuronal apoptosis, and increased neurogenesis; exo mainly taken up by microglia/macrophages | 163 | |
| BM-MSC-exo | BV2 microglia; promoted M1 to M2 phenotype and upregulated anti-inflammatory cytokines | mice; reduced cortical tissue apoptosis and inhibited neuroinflammation, possibly by exosomal miR-181b via IL-10/STAT3 pathway | 164 | |
| NSC-exo | NSCs; exo superior to parental cells | rats; improved neurobehavioral performance, inhibited astrocyte neuroinflammation, enhanced doublecortin neurogenesis, while maintaining SOX2 & Nestin stemness | 165 | |
| MSC-exo | N/A | rats; improved angiogenesis & neurogenesis, and sensorimotor & cognitive function, reduced neuroinflammation & hippocampal neuronal cell loss; 100 µg & 1 day were optimal | 166 | |
| Alzheimer’s disease | BM-MSC-exo | N/A | early-stage AD mice; reduced Aβ plaque burden & dystrophic neurites; carried neprilysin | 179 |
| BM-MSC-exo | primary neuron; reduced Aβ-induced iNOS expression | mice; rescued synaptic impairment and improved cognitive behavior | 180 | |
| NSC-exo | N/A | AD transgenic mice; enhanced mitochondrial function, sirtuin 1 activation, synaptic activity, decreased inflammatory response, and rescued cognitive deficits | 181 | |
| heat shock-induced NSC-exo | HC2S2 cells; exhibited greater neuroprotection against oxidative stress and Aβ-induced neurotoxicity | N/A | 182 | |
| MSC-exo | SH-SY5Y with FAD mutations; reduced Aβ expression and restored neuronal memory | AD transgenic mice; improved brain glucose metabolism and cognitive function; upregulated synapse-related genes & downregulated HDAC4 expression | 183 | |
| AF-MSC-exo | BV2 microglia, SH-SY5Y cells; mitigated neuroinflammatory microglial injury and recovered neurotoxicity from Aβ | N/A | 184 | |
| UC-MSC-exo | BV2 microglia; reduced inflammatory reaction & induced alternative microglial activation | mice; alleviated neuroinflammation and reduced Aβ deposition by modulating microglial activation; increased spatial learning & memory function | 185 | |
| MSC-exo | N/A | mice; stimulated neurogenesis in subventricular zone and alleviated Aβ-induced cognitive impairment | 186 | |
| NSC-exo | 5xFAD primary cerebral endothelial cells; reversed AD-caused BBB deficiency | 5xFAD mouse model; BBB breakdown occurred at 4 months of age, which could be mimicked with an in vitro BBB model | 188 | |
| RVG-tagged MSC-exo | N/A | transgenic APP/PS1 mice; improved CNS-targeted delivery; reduced Aβ deposition & astrocytes, and improved cognitive function; RVG-exo were better | 189 | |
| Parkinson’s disease | BM-MSC-exo | SH-SY5Y & SK-N-SH cells; exosomal TSG-6 attenuated MPP+-induced neurotoxicity via STAT3/miR-7/NEDD4 axis | N/A | 193 |
| NSC-exo | SH-SY5Y & BV2 cells; anti-oxidative stress, anti-inflammatory & anti-apoptotic effects | 6-hydroxydopamine-induced PD mice; protected dopaminergic cell viability via exosomal miR-182-5p, miR-183-5p, & miR-9 | 194 | |
| Multiple sclerosis | BM-MSC-exo | HAPI microglia; downregulated TNF-α & iNOS and upregulated IL-10, TGF-β and arginase-1 | EAE rat model; reduced inflammation and demyelination of CNS by regulating polarization of microglia from M1 to M2; decreased neurobehavioral scores and prevented weight loss | 197 |
| BM-MSC-exo | N/A | 2 mice models: EAE & CPZ; improved neurological outcome, increased OPC differentiation & remyelination, decreased neuroinflammation via TLR2 pathway | 198 | |
| Vascular dementia | NSC-exo | N/A | rats; exo-derived MIAT improved learning ability & memory via miR-34b-5p/calbindin-1 axis | 199 |
| HIV-associated neurocognitive disorders | NSC-exo | rescued cellular viability in HIV-damaged neurons, and inhibited apoptosis and inflammatory factor secretion | N/A | 200 |
| Radiation-induced cognitive dysfunction | NSC-exo | N/A | mice; exosomal miR-124 improved exercise & fear behavior, reversed cognitive impairment, and reduced neuroinflammation | 201 |
| NSC-exo | N/A | mice; protected host neurons, enhanced neurotrophic factors & synaptic signaling, and reduced neuroinflammation | 202 | |
| Epilepsy | BM-MSC-exo | N/A | mice; reduced hippocampal inflammation, and prevented abnormal neurogenesis & memory dysfunction | 203 |
| Mechanical allodynia | BM-MSC-exo | microglia; downregulated NOTCH2 which is targeted by exosomal miR-150-5p | L5 spinal nerve ligation rat model; increased paw withdrawal threshold and latency, reduced apoptosis and inflammation in spinal dorsal horn | 204 |
| Spina bifida aperta | NSC-exo | BM-MSCs; promoted neuronal differentiation of MSCs | rat embryo model; exosomal Netrin 1 promoted neuronal differentiation of MSCs & NSCs by upregulating Hand2/Phox2b | 205 |
| Depression | BM-MSc-exo | N/A | rats; suppressed apoptosis & boosted proliferation in hippocampal tissues by upregulating exosomal miR-26a | 206 |
| Stress | UC-MSc-exo | N/A | mice acute brain disorder model; increased adiponectin, improved cognitive function and hippocampal neurogenesis that was suppressed by streptozotocin injection | 207 |
| Brain ageing | NSC-exo | NSCs; rescued IRS-1/FoxO activation and counteracted reduced proliferation and senescence | mice; intranasal administration counteracted HFD-dependent impairment of adult hippocampal neurogenesis by restoring balance between proliferating and senescent NSCs | 208 |
| NSC-exo | NSCs; HFD downregulated CREB/BDNF/TrkB signaling | mice; intranasal administration restored CREB transcriptional activity, rescued both BDNF & HFD-dependent memory deficits | 209 | |
| hypothalamic NSC-exo | N/A | NSC-alation-induced mouse model; exosomal miRNAs reduced hypothalamic inflammation, and slowed down ageing, independent of food intake | 210 | |
| Deep hypothermic circulatory arrest | MSC-exo | primary rat brain endothelial cells; rescued OGD-induced injury & inhibited TLR4/NLRP3/caspase-1/ NF-κB pathway | N/A | 211 |
Aβ amyloid beta, AD Alzheimer’s disease, AF amniotic fluid, BBB blood brain barrier, BDNF brain-derived neurotrophic factor, BM bone marrow, CREB cAMP response element binding, CNS central nervous system, EAE experimental autoimmune encephalomyelitis, EDNRB endothelin receptor type B, exo exosome, FAD familial Alzheimer’s disease, FoxO Forkhead box O, H/R hypoxia and reoxygenation, HAPI highly aggressive proliferating immortalized, HDAC histone deacetylase, HFD high fat diet, HS hemorrhagic shock, iCM induced pluripotent stem cell-derived cardiomyocyte, IFN interferon, IL interleukin, iNOS inducible nitric oxide synthase, iPSC induced pluripotent stem cell, IRAK interleukin 1 receptor associated kinase, IRS insulin receptor substrate, LDH lactate dehydrogenase, MAPK mitogen-activated protein kinase, MCAO middle cerebral artery occlusion, MIAT myocardial infarction associated transcript, miR microRNA, MPP+ 1-methyl-4-phenylpyridinium, MSC mesenchymal stem cell, NEDD4 neuronally expressed developmentally down-regulated 4, NF-κB nuclear factor-kappa B, NLRP NOD-, LRR- and pyrin domain-containing protein, NSC neural stem cell, oe overexpressing, OGD oxygen- & glucose-deprived, SOX Sry-Box transcription factor, STAT signal transducer and activator of transcription, TGF transforming growth factor, TLR Toll-like receptor, TNF tumor necrosis factor, TRAF TNF receptor associated factor, TrkB tropomyosin receptor kinase B, TSG TNF stimulated gene, UC umbilical cord, Zeb zinc finger E-box binding homeobox