Disrupted blood-brain barrier in 5×FAD mouse model of Alzheimer’s disease can be mimicked and repaired in vitro with neural stem cell-derived exosomes

Li, Yanying; Huber, Christa C.; Wang, Hongmin

doi:10.1016/j.bbrc.2020.02.074

Cited by 31 publications

(19 citation statements)

References 16 publications

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“…Yet, we found no evidence of inflammatory suppression led by the MSC-exo. Previous studies in an AD model suggested that cognitive deficits rose due to inflamed blood-brain barrier (BBB), which was rescued post exosome treatment [47]. Based on our knowledge, the pathological and phenotypical abnormalities of the Shank3B KO mice are not caused by damages to the BBB but by the genetic mutation in the protein leading to synaptic dysfunction.…”

Section: Discussionmentioning

confidence: 72%

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B

et al. 2020

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Background: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan-McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular vesicle that contains important molecular information of the cell and are used for cell-to-cell communication. Within the fraction of the extracellular vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect. Methods: Exosomes derived from MSC (MSC-exo) were purified, characterized, and given via intranasal administration to Shank3B KO mice (in the concentration of 10 7 particles/ml). Three weeks post treatment, the mice were tested for behavioral scoring, and their results were compared with saline-treated control and their wild-type littermates. Results: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization, and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex. Conclusions: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mouse model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model of autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.

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Section: Discussionmentioning

confidence: 72%

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B

et al. 2020

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“…Yet, we found no evidence of in ammatory suppression led by the MSCexo. Previous studies in an AD model suggested that cognitive de cits rose due to in amed Blood-Brain Barrier (BBB), which was rescued post exosome treatment 47 . Based on our knowledge, the pathological and phenotypical abnormalities of the Shank3B KO mice are not caused by damages to the BBB but by the genetic mutation in the protein leads to synaptic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

Perets

Oron

Herman

et al. 2020

Preprint

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Background: Partial or an entire deletion of SHANK3 are considered as major drivers in the Phelan McDermid syndrome, in which 75% of patients are diagnosed with autism spectrum disorder (ASD). During the recent years, there was an increasing interest in stem cell therapy in ASD, and specifically, mesenchymal stem cells (MSC). Moreover, it has been suggested that the therapeutic effect of the MSC is mediated mainly via the secretion of small extracellular-vesicle that contain important molecular information of the cell and are used for cell-to cell communication. Within the fraction of the extracellular-vesicles, exosomes were highlighted as the most effective ones to convey the therapeutic effect.Methods: Exosomes derived from MSC (MSC-exo) were purified, characterized and given via intranasal administration to Shank3B KO mice (in concentration of 107 particals/ml). Three weeks post treatment the mice were tested for behavioral scoring and their results were compared to control saline treated and to their wild type littermates. Results: Intranasal treatment with MSC-exo improves the social behavior deficit in multiple paradigms, increases vocalization and reduces repetitive behaviors. We also observed an increase of GABARB1 in the prefrontal cortex.Conclusions: Herein, we hypothesized that MSC-exo would have a direct beneficial effect on the behavioral autistic-like phenotype of the genetically modified Shank3B KO mice model of autism. Taken together, our data indicate that intranasal treatment with MSC-exo improves the core ASD-like deficits of this mouse model autism and therefore has the potential to treat ASD patients carrying the Shank3 mutation.Limitations: Although the behavioral scoring of the MSC-exo treated group was significantly improved compared to their saline treated littermates, there is much more to learn regarding the mechanism of action of the MSC-exo.

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“…Exosomes also carry miR-132, which is established as a regulator of adherens-junction-related proteins, increasing BBB permeability and microhemorrhage events in brain microvasculature [ 44 ]. A recent study demonstrated that neural stem cell-derived exosomes can both initiate and repair BBB destruction, mitigating and reversing BBB-induced AD [ 45 ]. Such essential roles of exosomes in BBB integrity indicate an ever-increasing therapeutic value.…”

Section: Blood–brain Barrier (Bbb) and Blood–cerebrospinal Fluid Bmentioning

confidence: 99%

Unlocking the Power of Exosomes for Crossing Biological Barriers in Drug Delivery

2021

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Since the 2013 Nobel Prize was awarded for the discovery of vesicle trafficking, a subgroup of nanovesicles called exosomes has been driving the research field to a new regime for understanding cellular communication. This exosome-dominated traffic control system has increased understanding of many diseases, including cancer metastasis, diabetes, and HIV. In addition to the important diagnostic role, exosomes are particularly attractive for drug delivery, due to their distinctive properties in cellular information transfer and uptake. Compared to viral and non-viral synthetic systems, the natural, cell-derived exosomes exhibit intrinsic payload and bioavailability. Most importantly, exosomes easily cross biological barriers, obstacles that continue to challenge other drug delivery nanoparticle systems. Recent emerging studies have shown numerous critical roles of exosomes in many biological barriers, including the blood–brain barrier (BBB), blood–cerebrospinal fluid barrier (BCSFB), blood–lymph barrier (BlyB), blood–air barrier (BAB), stromal barrier (SB), blood–labyrinth barrier (BLaB), blood–retinal barrier (BRB), and placental barrier (PB), which opens exciting new possibilities for using exosomes as the delivery platform. However, the systematic reviews summarizing such discoveries are still limited. This review covers state-of-the-art exosome research on crossing several important biological barriers with a focus on the current, accepted models used to explain the mechanisms of barrier crossing, including tight junctions. The potential to design and engineer exosomes to enhance delivery efficacy, leading to future applications in precision medicine and immunotherapy, is discussed.

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Disrupted blood-brain barrier in 5×FAD mouse model of Alzheimer’s disease can be mimicked and repaired in vitro with neural stem cell-derived exosomes

Cited by 31 publications

References 16 publications

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mouse model of autism Shank3B

Exosomes derived from mesenchymal stem cells improved core symptoms of genetically modified mice model of autism Shank3B

Unlocking the Power of Exosomes for Crossing Biological Barriers in Drug Delivery

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