A single intranasal dose of human mesenchymal stem cell-derived extracellular vesicles after traumatic brain injury eases neurogenesis decline, synapse loss, and BDNF-ERK-CREB signaling
Abstract:An optimal intranasal (IN) dose of human mesenchymal stem cell-derived extracellular vesicles (hMSC-EVs), 90 min post-traumatic brain injury (TBI), has been reported to prevent the evolution of acute neuroinflammation into chronic neuroinflammation resulting in the alleviation of long-term cognitive and mood impairments. Since hippocampal neurogenesis decline and synapse loss contribute to TBI-induced long-term cognitive and mood dysfunction, this study investigated whether hMSC-EV treatment after TBI can prev… Show more
“…23,24 Intranasal (IN) administration of human MSC-derived extracellular vesicles in traumatic brain injury (TBI) mice increases neurogenesis in the sub-ventricular zone (SVZ) by increasing cell proliferation and enhancing the expression of DCX and NeuN. 25 Pourhadi et al also demonstrated that intranasal exosomes reduce amyloid-beta deposits and increase hippocampus preand post-synaptic protein expression to improve spatial memory in Alzheimer's disease model. 26 Based on the above, we aimed to investigate the impact of intravenous exosome delivery on cognitive function and neurogenesis markers in the DG and CA1 region of the hippocampus in METHtreated mice.…”
Section: Introductionmentioning
confidence: 99%
“…They also offer protection to the nervous system against oxidative damage in several neurological diseases 23,24 . Intranasal (IN) administration of human MSC‐derived extracellular vesicles in traumatic brain injury (TBI) mice increases neurogenesis in the sub‐ventricular zone (SVZ) by increasing cell proliferation and enhancing the expression of DCX and NeuN 25 . Pourhadi et al.…”
BackgroundMethamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH‐induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)‐derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs‐derived exosomes on cognitive function and neurogenesis of METH‐addicted rodents.MethodsMale BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs‐derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis‐related factors, including NeuN and DCX, and the expression of Iba‐1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF‐α and NF‐κB, were evaluated by western blotting.ResultsThe results showed that BMSCs‐exosomes improved the time spent in the target quadrant and correct‐to‐wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF‐α and NF‐κB. Besides, BMSC‐exosomes down‐regulated the expression of Iba‐1.ConclusionOur findings indicate that BMSC‐exosomes mitigated METH‐caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.
“…23,24 Intranasal (IN) administration of human MSC-derived extracellular vesicles in traumatic brain injury (TBI) mice increases neurogenesis in the sub-ventricular zone (SVZ) by increasing cell proliferation and enhancing the expression of DCX and NeuN. 25 Pourhadi et al also demonstrated that intranasal exosomes reduce amyloid-beta deposits and increase hippocampus preand post-synaptic protein expression to improve spatial memory in Alzheimer's disease model. 26 Based on the above, we aimed to investigate the impact of intravenous exosome delivery on cognitive function and neurogenesis markers in the DG and CA1 region of the hippocampus in METHtreated mice.…”
Section: Introductionmentioning
confidence: 99%
“…They also offer protection to the nervous system against oxidative damage in several neurological diseases 23,24 . Intranasal (IN) administration of human MSC‐derived extracellular vesicles in traumatic brain injury (TBI) mice increases neurogenesis in the sub‐ventricular zone (SVZ) by increasing cell proliferation and enhancing the expression of DCX and NeuN 25 . Pourhadi et al.…”
BackgroundMethamphetamine (METH) is a psychostimulant substance with highly addictive and neurotoxic effects, but no ideal treatment option exists to improve METH‐induced neurocognitive deficits. Recently, mesenchymal stem cells (MSCs)‐derived exosomes have raised many hopes for treating neurodegenerative sequela of brain disorders. This study aimed to determine the therapeutic potential of MSCs‐derived exosomes on cognitive function and neurogenesis of METH‐addicted rodents.MethodsMale BALB/c mice were subjected to chronic METH addiction, followed by intravenous administration of bone marrow MSCs‐derived exosomes. Then, the spatial memory and recognition memory of animals were assessed by the Barnes maze and the novel object recognition test (NORT). The neurogenesis‐related factors, including NeuN and DCX, and the expression of Iba‐1, a microglial activation marker, were assessed in the hippocampus by immunofluorescence staining. Also, the expression of inflammatory cytokines, including TNF‐α and NF‐κB, were evaluated by western blotting.ResultsThe results showed that BMSCs‐exosomes improved the time spent in the target quadrant and correct‐to‐wrong relative time in the Barnes maze. Also, NORT's discrimination index (DI) and recognition index (RI) were improved following exosome therapy. Additionally, exosome therapy significantly increased the expression of NeuN and DCX in the hippocampus while decreasing the expression of inflammatory cytokines, including TNF‐α and NF‐κB. Besides, BMSC‐exosomes down‐regulated the expression of Iba‐1.ConclusionOur findings indicate that BMSC‐exosomes mitigated METH‐caused cognitive dysfunction by improving neurogenesis and inhibiting neuroinflammation in the hippocampus.
“…Thus, normalized neurogenesis in LPS-treated mice receiving hiPSC-NSC-EVs is likely a downstream beneficial effect of EVs suppressing neuroinflammation. However, involvement of pro-neurogenic pathways, such as the activation of brain-derived neurotrophic factor-extracellular signal-regulated kinase-cyclic AMP response-element binding protein signaling, as observed in a traumatic brain injury model following the administration of human bone marrow mesenchymal stem cell-derived EVs, cannot be ruled out [ 48 ]. Such possibility is supported by hiPSC-NSC-EVs exhibiting enriched payload of proteins such as agrin efficient in promoting CREB activation [ 89 ] and agrin and PTX3 capable of directly enhancing neurogenesis [ 90 , 102 ].…”
Section: Discussionmentioning
confidence: 99%
“…Our previous studies have detailed immunohistochemical methods employed in this study [ 35 , 48 , 49 ]. In each animal, every 15th or 20th section through the whole hippocampus was processed for immunohistochemical identification of IBA-1 + microglia, GFAP + astrocytes, BrdU-positive newly born cells and doublecortin (DCX) positive newly generated neurons.…”
Section: Methodsmentioning
confidence: 99%
“…We employed western blots of hippocampal tissue lysates to quantify Syn and PSD95, as described in our recently published study [ 48 ]. The proteins in the membranes were identified using antibodies against Syn (1:5000, ProteinTech, Rosemont, IL, USA), PSD95 (1:1000, Abcam), and β-tubulin (1:10,000, Abcam) after being transferred onto a nitrocellulose membrane using the iBlot2 gel transfer device (ThermoFisher Scientific).…”
Extracellular vesicles (EVs) released by human induced pluripotent stem cell-derived neural stem cells (hiPSC-NSCs) are enriched with miRNAs and proteins capable of mediating robust antiinflammatory activity. The lack of tumorigenic and immunogenic properties and ability to permeate the entire brain to incorporate into microglia following intranasal (IN) administrations makes them an attractive biologic for curtailing chronic neuroinflammation in neurodegenerative disorders. We tested the hypothesis that IN administrations of hiPSC-NSC-EVs can alleviate chronic neuroinflammation and cognitive impairments induced by the peripheral lipopolysaccharide (LPS) challenge. Adult male, C57BL/6J mice received intraperitoneal injections of LPS (0.75 mg/kg) for seven consecutive days. Then, the mice received either vehicle (VEH) or hiPSC-NSC-EVs (~ 10 × 109 EVs/administration, thrice over 6 days). A month later, mice in all groups were investigated for cognitive function with behavioral tests and euthanized for histological and biochemical studies. Mice receiving VEH after LPS displayed deficits in associative recognition memory, temporal pattern processing, and pattern separation. Such impairments were associated with an increased incidence of activated microglia presenting NOD-, LRR-, and pyrin domain containing 3 (NLRP3) inflammasomes, elevated levels of NLRP3 inflammasome mediators and end products, and decreased neurogenesis in the hippocampus. In contrast, the various cognitive measures in mice receiving hiPSC-NSC-EVs after LPS were closer to naive mice. Significantly, these mice displayed diminished microglial activation, NLRP3 inflammasomes, proinflammatory cytokines, and a level of neurogenesis matching age-matched naïve controls. Thus, IN administrations of hiPSC-NSC-EVs are an efficacious approach to reducing chronic neuroinflammation-induced cognitive impairments.
Altered expression of multiple miRNAs was found to be extensively involved in the pathogenesis of different neurological disorders including Alzheimer's disease, Parkinson's disease, stroke, epilepsy, multiple sclerosis, amyotrophic lateral sclerosis, and Huntington's disease. One of the biggest concerns within gene‐based therapy is the delivery of the therapeutic microRNAs to the intended place, which is obligated to surpass the biological barriers without undergoing degradation in the bloodstream or renal excretion. Hence, the delivery of modified and unmodified miRNA molecules using excellent vehicles is required. In this light, mesenchymal stem cells (MSCs) have attracted increasing attention. The MSCs can be genetically modified to express or overexpress a particular microRNA aimed with promote neurogenesis and neuroprotection. The current review has focused on the therapeutic capabilities of microRNAs‐overexpressing MSCs to ameliorate functional deficits in neurological conditions.
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